Compounds useful for treating gastrointestinal tract disorders

ABSTRACT

The present disclosure is directed to compounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/476,836 that was filed on Jul. 9, 2019, which is a 35 U.S.C. § 371application of International Application Serial No. PCT/US2018/013020that was filed filed on Jan. 9, 2018, which claims priority to U.S.provisional patent application No. 62/444,335 that was filed on 9 Jan.2017, and U.S. provisional patent application No. 62/541,097 that wasfiled on Aug. 4, 2017. The entire content of the applications referencedabove is hereby incorporated by reference herein.

FIELD OF INVENTION

The present disclosure is directed to indanes derivatives that aresubstantially active in the gastrointestinal tract to inhibitNHE-mediated antiport of sodium ions and hydrogen ions, and the use ofsuch compounds in the treatment of disorders associated with fluidretention or salt overload and in the treatment of gastrointestinaltract disorders, including the treatment or reduction of pain associatedwith a gastrointestinal tract disorder.

BACKGROUND OF THE INVENTION

Disorders Associated with Fluid Retention and Salt Overload

According to the American Heart Association, more than 5 millionAmericans have suffered from heart failure, and an estimated 550,000cases of congestive heart failure (CHF) occur each year (Schocken, D. D.et al., Prevention of heart failure: a scientific statement from theAmerican Heart Association Councils on Epidemiology and Prevention,Clinical Cardiology, Cardiovascular Nursing, and High Blood PressureResearch; Quality of Care and Outcomes Research InterdisciplinaryWorking Group; and Functional Genomics and Translational BiologyInterdisciplinary Working Group: Circulation, v. 117, no. 19, p.2544-2565 (2008)). The clinical syndrome of congestive heart failureoccurs when cardiac dysfunction prevents adequate perfusion ofperipheral tissues. The most common form of heart failure leading to CHFis systolic heart failure, caused by contractile failure of themyocardium. A main cause of CHF is due to ischemic coronary arterydisease, with or without infarction. Long standing hypertension,particularly when it is poorly controlled, may lead to CHF.

In patients with CHF, neurohumoral compensatory mechanisms (i.e., thesympathetic nervous system and the renin-angiotensin system) areactivated in an effort to maintain normal circulation. Therenin-angiotensin system is activated in response to decreased cardiacoutput, causing increased levels of plasma renin, angiotensin II, andaldosterone. As blood volume increases in the heart, cardiac outputincreases proportionally, to a point where the heart is unable to dilatefurther. In the failing heart, contractility is reduced, so the heartoperates at higher volumes and higher filling pressures to maintainoutput. Filling pressures may eventually increase to a level that causestransudation of fluid into the lungs and congestive symptoms (e.g.,edema, shortness of breath). All of these symptoms are related to fluidvolume and salt retention, and this chronic fluid and salt overloadfurther contribute to disease progression.

Compliance with the medication regimen and with dietary sodiumrestrictions is a critical component of self-management for patientswith heart failure and may lengthen life, reduce hospitalizations andimprove quality of life. Physicians often recommend keeping salt intakebelow 2.3 g per day and no more than 2 g per day for people with heartfailure. Most people eat considerably more than this, so it is likelythat a person with congestive heart failure will need to find ways toreduce dietary salt.

A number of drug therapies currently exist for patients suffering fromCHF. For example, diuretics may be used or administered to relievecongestion by decreasing volume and, consequently, filling pressures tobelow those that cause pulmonary edema. By counteracting the volumeincrease, diuretics reduce cardiac output; however, fatigue anddizziness may replace CHF symptoms. Among the classes or types ofdiuretics currently being used is thiazides. Thiazides inhibit NaCltransport in the kidney, thereby preventing reabsorption of Na in thecortical diluting segment at the ending portion of the loop of Henle andthe proximal portion of the distal convoluted tubule. However, thesedrugs are not effective when the glomerular filtration rate (GFR) isless than 30 ml/min. Additionally, thiazides, as well as otherdiuretics, may cause hypokalemia. Also among the classes or types ofdiuretics currently being used is loop diuretics (e.g., furosemide).These are the most potent diuretics and are particularly effective intreating pulmonary edema. Loop diuretics inhibit the NaKCl transportsystem, thus preventing reabsorption of Na in the loop of Henle.

Patients that have persistent edema despite receiving high doses ofdiuretics may be or become diuretic-resistant. Diuretic resistance maybe caused by poor availability of the drug. In patients with renalfailure, which has a high occurrence in the CHF population, endogenousacids compete with loop diuretics such as furosemide for the organicacid secretory pathway in the tubular lumen of the nephron. Higherdoses, or continuous infusion, are therefore needed to achieve entranceof an adequate amount of drug into the nephron. However, recentmeta-analysis has raised awareness about the long-term risk of chronicuse of diuretics in the treatment of CHF. For instance, in a recentstudy (Ahmed et al., Int J Cardiol. 2008 Apr. 10; 125(2): 246-253) itwas shown that chronic diuretic use was associated with significantlyincreased mortality and hospitalization in ambulatory older adults withheart failure receiving angiotensin converting enzyme inhibitor anddiuretics.

Angiotensin-converting enzyme (“ACE”) inhibitors are an example ofanother drug therapy that may be used to treat congestive heart failure.ACE inhibitors cause vasodilatation by blocking therenin-angiotensin-aldosterone system. Abnormally low cardiac output maycause the renal system to respond by releasing renin, which thenconverts angiotensinogen into angiotensin I. ACE converts angiotensin Iinto angiotensin II. Angiotensin II stimulates the thirst centers in thehypothalamus and causes vasoconstriction, thus increasing blood pressureand venous return. Angiotensin II also causes aldosterone to bereleased, causing reabsorption of Na and concomitant passivereabsorption of fluid, which in turn causes the blood volume toincrease. ACE inhibitors block this compensatory system and improvecardiac performance by decreasing systemic and pulmonary vascularresistance. ACE inhibitors have shown survival benefit andconventionally have been a treatment of choice for CHF. However, sinceACE inhibitors lower aldosterone, the K-secreting hormone, one of theside-effects of their use is hyperkalemia. In addition, ACE inhibitorshave been show to lead to acute renal failure in certain categories ofCHF patients. (See, e.g., C. S. Cruz et al., “Incidence and Predictorsof Development of Acute Renal Failure Related to the Treatment ofCongestive Heart Failure with ACE Inhibitors, Nephron Clin. Pract., v.105, no. 2, pp c77-c83 (2007)).

Patients with end stage renal disease (“ESRD”), i.e., stage 5 chronickidney failure, must undergo hemodialysis three times per week. Thequasi-absence of renal function and ability to eliminate salt and fluidresults in large fluctuations in body weight as fluid and salt build upin the body (sodium/volume overload). The fluid overload ischaracterized as interdialytic weight gain. High fluid overload is alsoworsened by heart dysfunction, specifically CHF. Dialysis is used toremove uremic toxins and also adjust salt and fluid homeostasis.However, symptomatic intradialytic hypotension (SIH) may occur whenpatients are over-dialyzed. SIH is exhibited in about 15% to 25% of theESRD population (Davenport, A., C. Cox, and R. Thuraisingham, Bloodpressure control and symptomatic intradialytic hypotension in diabetichaemodialysis patients: a cross-sectional survey; Nephron Clin. Pract.,v. 109, no. 2, p. c65-c71 (2008)). Like in hypertensive and CHFpatients, dietary restrictions of salt and fluid are highly recommendedbut poorly followed because of the poor palatability of low-salt food

The cause of primary or “essential” hypertension is elusive. However,several observations point to the kidney as a primary factor. Thestrongest data for excess salt intake and elevated blood pressure comefrom INTERSALT, a cross-sectional study of greater than 10,000participants. For individuals, a significant, positive, independentlinear relation between 24-hour sodium excretion and systolic bloodpressure was found. Higher individual 24-hour urinary sodium excretionswere found to be associated with higher systolic/diastolic bloodpressure on average, by 6-3/3-0 mm Hg. Primary hypertension is a typicalexample of a complex, multifactorial, and polygenic trait. All thesemonogenic hypertensive syndromes are virtually confined to mutated genesinvolving gain of function of various components of therenin-angiotensin-aldosterone system, resulting in excessive renalsodium retention. In a broad sense, these syndromes are characterized byincreased renal sodium reabsorption arising through either primarydefects in sodium transport systems or stimulation of mineralocorticoidreceptor activity (Altun, B., and M. Arici, 2006, Salt and bloodpressure: time to challenge; Cardiology, v. 105, no. 1, p. 9-16 (2006)).A much larger number of controlled studies have been performed onhypertensive subjects during the last three decades to determine whethersodium reduction will reduce established high blood pressure.Meta-analyses of these studies have clearly shown a large decrease inblood pressure in hypertensive patients.

In end stage liver disease (ESLD), accumulation of fluid as ascites,edema or pleural effusion due to cirrhosis is common and results from aderangement in the extracellular fluid volume regulatory mechanisms.Fluid retention is the most frequent complication of ESLD and occurs inabout 50% of patients within 10 years of the diagnosis of cirrhosis.This complication significantly impairs the quality of life of cirrhoticpatients and is also associated with poor prognosis. The one-year andfive-year survival rate is 85% and 56%, respectively (Kashani et al.,Fluid retention in cirrhosis: pathophysiology and management; QJM, v.101, no. 2, p. 71-85 (2008)). The most acceptable theories postulatethat the initial event in ascites formation in the cirrhotic patient issinusoidal hypertension. Portal hypertension due to an increase insinusoidal pressure activates vasodilatory mechanisms. In advancedstages of cirrhosis, arteriolar vasodilation causes underfilling ofsystemic arterial vascular space. This event, through a decrease ineffective blood volume, leads to a drop in arterial pressure.Consequently, baroreceptor-mediated activation of renin-angiotensinaldosterone system, sympathetic nervous system and nonosmotic release ofamidiuretic hormone occur to restore the normal blood homeostasis. Theseevents cause further retention of renal sodium and fluid. Splanchnicvasodilation increases splanchnic lymph production, exceeding the lymphtransportation system capacity, and leads to lymph leakage into theperitoneal cavity. Persistent renal sodium and fluid retention,alongside increased splanchnic vascular permeability in addition tolymph leakage into the peritoneal cavity, play a major role in asustained ascites formation.

Thiazolidinediones (TZD's), such as rosiglitazone, are peroxisomeproliferator-activated receptor (PPAR) gamma agonist agents used for thetreatment of type-2 diabetes and are widely prescribed. Unfortunately,fluid retention has emerged as the most common and serious side-effectof TZD's and has become the most frequent cause of discontinuation oftherapy. The incidence of TZD-induced fluid retention ranges from 7% inmonotherapy and to as high as 15% when combined with insulin (Yan, T.,Soodvilai, S., PPAR Research volume 2008, article ID 943614). Themechanisms for such side-effects are not fully understood but may berelated in Na and fluid re-absorption in the kidney. However TZD-inducedfluid retention is resistant to loop diuretics or thiazide diuretics,and combination of peroxisome proliferator-activated receptor (PPAR)alpha with PPAR gamma agonists, which were proposed to reduce such fluidoverload, are associated with major adverse cardiovascular events.

In view of the foregoing, it is recognized that salt and fluidaccumulation contribute to the morbidity and mortality of many diseases,including heart failure (in particular, congestive heart failure),chronic kidney disease, end-stage renal disease, liver disease and thelike. It is also accepted that salt and fluid accumulation are riskfactors for hypertension. Accordingly, there is a clear need for amedicament that, when administered to a patient in need, would result ina reduction in sodium retention, fluid retention, or both. Such amedicament would also not involve or otherwise impair renal mechanismsof fluid/Na homeostasis.

One option to consider for treating excessive fluid overload is toinduce diarrhea. Diarrhea may be triggered by several agents including,for example, laxatives such as sorbitol, polyethyleneglycol, bisacodyland phenolphthaleine. Sorbitol and polyethyleneglycol triggers osmoticdiarrhea with low levels of secreted electrolytes; thus, their utilityin removing sodium salt from the GI tract is limited. The mechanism ofaction of phenolphthalein is not clearly established, but is thought tobe caused by inhibition of the Na/K ATPase and the C/HCO₃ anionexchanger and stimulation of electrogenic anion secretion (see, e.g.,Eherer, A. J., C. A. Santa Ana, J. Porter, and J. S. Fordtran, 1993,Gastroenterology, v. 104, no. 4, p. 1007-1012). However, some laxatives,such as phenolphthalein, are not viable options for the chronictreatment of fluid overload, due to the potential risk ofcarcinogenicity in humans. Furthermore, laxatives may not be usedchronically, as they have been shown to be an irritant and cause mucosaldamage. Accordingly, it should also be recognized that the induction ofchronic diarrhea as part of an effort to control salt and fluid overloadwould be an undesired treatment modality for most patients. Anymedicament utilizing the GI tract for this purpose would therefore needto control diarrhea in order to be of practical benefit.

One approach for the treatment of mild diarrhea is the administration ofa fluid-absorbing polymer, such as the natural plant fiber psyllium.Polymeric materials, and more specifically hydrogel polymers, may alsobe used for the removal of fluid from the gastrointestinal (GI) tract.The use of such polymers is described in, for example, U.S. Pat. Nos.4,470,975 and 6,908,609, the entire contents of which are incorporatedherein by reference for all relevant and consistent purposes. However,for such polymers to effectively remove significant quantities of fluid,they must desirably resist the static and osmotic pressure rangeexisting in the GI tract. Many mammals, including humans, make a softfeces with a water content of about 70%, and do so by transporting fluidagainst the high hydraulic resistance imposed by the fecal mass. Severalstudies show that the pressure required to dehydrate feces from about80% to about 60% is between about 500 kPa and about 1000 kPa (i.e.,about 5 to about 10 atm). (See, e.g., McKie, A. T., W. Powrie, and R. J.Naftalin, 1990, Am J Physiol, v. 258, no. 3 Pt 1, p. G391-G394;Bleakman, D., and R. J. Naftalin, 1990, Am J Physiol, v. 258, no. 3 Pt1, p. G377-G390; Zammit, P. S., M. Mendizabal, and R. J. Naftalin, 1994,J Physiol, v. 477 (Pt 3), p. 539-548.) However, the static pressuremeasured intraluminally is usually between about 6 kPa and about 15 kPa.The rather high pressure needed to dehydrate feces is essentially due toan osmotic process and not a mechanical process produced by muscularforces. The osmotic pressure arises from the active transport of saltacross the colonic mucosa that ultimately produces a hypertonic fluidabsorption. The osmotic gradient produced drives fluid from the lumen tothe serosal side of the mucosa. Fluid-absorbing polymers, such as thosedescribed in for example U.S. Pat. Nos. 4,470,975 and 6,908,609, may notbe able to sustain such pressure. Such polymers may collapse in a normalcolon where the salt absorption process is intact, hence removing amodest quantity of fluid and thereby salt.

Synthetic polymers that bind sodium have also been described. Forexample, ion-exchange polymeric resins, such as Dowex-type cationexchange resins, have been known since about the 1950's. However, withthe exception of Kayexalate™ (or Kionex™), which is a polystyrenesulfonate salt approved for the treatment of hyperkalemia, cationexchange resins have very limited use as drugs, due at least in part totheir limited capacity and poor cation binding selectivity.Additionally, during the ion-exchange process, the resins may release astoichiometric amount of exogenous cations (e.g., H, K, Ca), which mayin turn potentially cause acidosis (H), hyperkalemia (K) or contributeto vascular calcification (Ca). Such resins may also cause constipation.

Gastrointestinal Tract Disorders

Constipation is characterized by infrequent and difficult passage ofstool and becomes chronic when a patient suffers specified symptoms forover 12 non-consecutive weeks within a 12-month period. Chronicconstipation is idiopathic if it is not caused by other diseases or byuse of medications. An evidence-based approach to the management ofchronic constipation in North America (Brandt et al., 2005, Am. J.Gastroenterol. 100(Suppl.1):S5-S21) revealed that prevalence isapproximately 15% of the general population. Constipation is reportedmore commonly in women, the elderly, non-whites, and individuals fromlower socioecyanomic groups.

Irritable bowel syndrome (IBS) is a common GI disorder associated withalterations in motility, secretion and visceral sensation. A range ofclinical symptoms characterizes this disorder, including stool frequencyand form, abdominal pain and bloating. The recognition of clinicalsymptoms of IBS are yet to be defined, but it is now common to refer todiarrhea-predominant IBS (D-IBS) and constipation-predominant IBS(C-IBS), wherein D-IBS is defined as continuous passage of loose orwatery stools and C-IBS as a group of functional disorders which presentas difficult, infrequent or seemingly incomplete defecation. Thepathophysiology of IBS is not fully understood, and a number ofmechanisms have been suggested. Visceral hypersensitivity is oftenconsidered to play a major etiologic role and has been proposed to be abiological marker even useful to discriminate IBS from other causes ofabdominal pain. In a recent clinical study (Posserud, 1. et al,Gastroenterology, 2007:133:1113-1123) IBS patients were submitted to avisceral sensitivity test (Balloon distention) and compared with healthysubjects. It revealed that 61% of the IBS patients had an alteredvisceral perception as measured by pain and discomfort threshold. Otherreviews have documented the role of visceral hypersensitivity inabdominal pain symptomatic of various gastrointestinal tract disorders(Akbar, A, et al, Aliment. Pharmaco. Ther., 2009, 30, 423-435; Bueno etal., Neurogastroenterol Motility (2007) 19 (suppl.1), 89-119). Colonicand rectal distention have been widely used as a tool to assess visceralsensitivity in animal and human studies. The type of stress used toinduce visceral sensitivity varies upon the models (see for instanceEutamen, H Neurogastroenterol Motil. 2009 Aug. 25. [Epub ahead ofprint]), however stress such as Partial restraint stress (PRS) is arelatively mild, non-ulcerogenic model that is considered morerepresentative of the IBS setting.

Constipation is commonly found in the geriatric population, particularlypatients with osteoporosis who have to take calcium supplements. Calciumsupplements have shown to be beneficial in ostoporotic patients torestore bone density but compliance is poor because of calcium-inducedconstipation effects.

Opioid-induced constipation (OIC) (also referred to as opioid-inducedbowel dysfunction or opioid bowel dysfuntion (OBD)) is a common adverseeffect associated with opioid therapy. OIC is commonly described asconstipation; however, it is a constellation of adverse gastrointestinal(GI) effects, which also includes abdominal cramping, bloating, andgastroesophageal reflux. Patients with cancer may have disease-relatedconstipation, which is usually worsened by opioid therapy. However, OICis not limited to cancer patients. A recent survey of patients takingopioid therapy for pain of non-cancer origin found that approximately40% of patients experienced constipation related to opioid therapy (<3complete bowel movements per week) compared with 7.6% in a controlgroup. Of subjects who required laxative therapy, only 46% ofopioid-treated patients (control subjects, 84%) reported achieving thedesired treatment results >50% of the time (Pappagallo, 2001, Am. J.Surg. 182(5A Suppl.):11S-18S).

Some patients suffering from chronic idiopathic constipation can besuccessfully treated with lifestyle modification, dietary changes andincreased fluid and fiber intake, and these treatments are generallytried first. For patients who fail to respond to these approaches,physicians typically recommend laxatives, most of which are availableover-the-counter. Use of laxatives provided over-the-counter is judgedinefficient by about half of the patients (Johanson and Kralstein, 2007,Aliment. Pharmacol. Ther. 25(5):599-608). Other therapeutic optionscurrently prescribed or in clinical development for the treatment of IBSand chronic constipation including OIC are described in, for example:Chang et al., 2006, Curr. Teat. Options Gastroenterol. 9(4):314-323;Gershon and Tack, 2007, Gastroenterology 132(1):397-414; and, Hammerleand Surawicz, 2008, World J. Gastroenterol. 14(17):2639-2649. Suchtreatments include but are not limited to serotonin receptor ligands,chloride channel activators, opioid receptor antagonists,guanylate-cyclase receptor agonists and nucleotide P2Y(2) receptoragonists. Many of these treatment options are inadequate, as they may behabit forming, ineffective in some patients, may cause long term adverseeffects, or otherwise are less than optimal.

Na⁺/H⁺ Exchanger (NHE) Inhibitors

A major function of the GI tract is to maintain water/Na homeostasis byabsorbing virtually all water and Na to which the GI tract is exposed.The epithelial layer covering the apical surface of the mammalian colonis a typical electrolyte-transporting epithelium, which is able to movelarge quantities of salt and water in both directions across the mucosa.For example, each day the GI tract processes about 9 liters of fluid andabout 800 meq of Na. (See, e.g., Zachos et al., Molecular physiology ofintestinal Na ⁺/H⁺ exchange; Annu. Rev. Physiol., v. 67, p. 411-443(2005).) Only about 1.5 liters of this fluid and about 150 meq of thissodium originates from ingestion; rather, the majority of the fluid(e.g., about 7.5 liters) and sodium (about 650 meq) is secreted via theGI organs as part of digestion. The GI tract therefore represents aviable target for modulating systemic sodium and fluid levels.

Many reviews have been published on the physiology and secretory and/orabsorption mechanisms of the GI tract (see, e.g., Kunzelmann et al.,Electrolyte transport in the mammalian colon: mechanisms andimplications for disease; Physiol. Rev., v. 82, no. 1, p. 245-289(2002); Geibel, J. P.; Secretion and absorption by colonic crypts; Annu.Rev. Physiol, v. 67, p. 471-490 (2005); Zachos et al., supra; Kiela, P.R. et al., Apical NA ⁺/H⁺ exchangers in the mammalian gastrointestinaltract; J. Physiol. Pharmacol., v. 57 Suppl. 7, p. 51-79 (2006)). The twomain mechanisms of Na absorption are electroneutral and electrogenictransport. Electroneutral transport is essentially due to the Na⁺/H⁺antiport NHE (e.g., NHE-3) and is responsible for the bulk of Naabsorption. Electrogenic transport is provided by the epithelium sodiumchannel (“ENaC”). Electroneutral transport is located primarily in theileal segment and proximal colon and electrogenic transport is locatedin the distal colon.

Plasma membrane NHEs contribute to maintenance of intracellular pH andvolume, transcellular absorption of NaCl and NaHCO₃, and fluid balancecarried out by epithelial cells, especially in the kidney, intestine,gallbladder, and salivary glands, as well as regulation of systemic pH.There exists a body of literature devoted to the role and clinicalintervention on systemic NHEs to treat disorders related to ischemia andreperfusion for cardioprotection or renal protection. Nine isoforms ofNHEs have been identified (Kiela, P. R., et al.; Apical NA ⁺ /H ⁺exchangers in the mammalian gastrointestinal tract; J. Physiol.Pharmacol., v. 57 Suppl 7, p. 51-79 (2006)), of which NHE-2, NHE-3 andNHE-8 are expressed on the apical side of the GI tract, with NHE-3providing a larger contribution to transport. Another, yet to beidentified, Cl-dependant NHE has been identified in the crypt of ratcells. In addition, much research has been devoted to identifyinginhibitors of NHEs. The primary targets of such research have been NHE-1and NHE-3. Small molecule NHE inhibitors are, for example, described in:U.S. Pat. Nos. 5,866,610; 6,399,824; 6,911,453; 6,703,405; 6,005,010;6,736,705; 6,887,870; 6,737,423; 7,326,705; 5,824,691 (WO 94/026709);6,399,824 (WO 02/024637); U.S. Pat. Pub. Nos. 2004/0039001 (WO02/020496); 2005/0020612 (WO 03/055490); 2004/0113396 (WO 03/051866);2005/0020612; 2005/0054705; 2008/0194621; 2007/0225323; 2004/0039001;2004/0224965; 2005/0113396; 2007/0135383; 2007/0135385; 2005/0244367;2007/0270414; International Publication Nos. WO 01/072742; WO 01/021582(CA2387529); WO 97/024113 (CA02241531) and European Pat. No. EP0744397(CA2177007); all of which are incorporated herein by reference in theirentirety for all relevant and consistent purposes.

However, such research failed to develop or recognize the value orimportance of NHE inhibitors that are not absorbed (i.e., not systemic)and target the gastrointestinal tract, as disclosed recently in WO2010/078449. Such inhibitors can be utilized in the treatment ofdisorders associated with fluid retention and salt overload and in thetreatment of GI tract disorders, including the treatment or reduction ofpain associated with a gastrointestinal tract disorder. Such inhibitorsare particular advantageous because they can be delivered with reducedfear of systemic on-target or off-target effects (e.g., little or norisk of renal involvement or other systemic effects.

Accordingly, while progress has been made in the foregoing fields, thereremains a need in the art for novel compounds for use in the disordersassociated with fluid retention and salt overload and in the treatmentof gastrointestinal tract disorders, including the treatment orreduction of pain associated with a gastrointestinal tract disorder. Thepresent invention fulfills this need and provides further relatedadvantages.

SUMMARY OF THE INVENTION

In brief, the present invention is directed to compounds that aresubstantially active in the gastrointestinal tract to inhibitNHE-mediated antiport of sodium ions and hydrogen ions, and the use ofsuch compounds in the treatment of disorders associated with fluidretention and salt overload and in the treatment of gastrointestinaltract disorders, including the treatment or reduction of pain associatedwith a gastrointestinal tract disorder.

A compound of formula I:

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,isomer, or tautomer thereof, wherein:

Linker is —R¹³—(CHR¹³)_(p)—[Y—(CH₂)_(r)]_(s)—Z—R¹³—(CH₂)_(t)—Z—;

X is a bond, H, N, O, CR¹¹R¹², CR¹¹, C, —NHC(O)NH—, —(CHR¹³)_(p)— orC₃-C₆cyclolakyl;

W is independently, at each occurrence, S(O)₂, C(O), or —(CH₂)_(m)—;

Z is independently, at each occurrence, a bond, C(O), or —C(O)NH—;

Y is independently, at each occurrence, O, S, NH, N(C₁-C₃alkyl), or—C(O)NH—;

Q is a bond, NH, —C(O)NH—, —NHC(O)NH—, —NHC(O)N(CH₃)—, or—NHC(O)NH—(CHR¹³);

m is an integer from 1 to 2;

n is an integer from 1 to 4;

r and p are independently, at each occurrence, integers from 0 to 8;

s is an integer from 0 to 4;

t is an integer from 0 to 4;

u is an integer from 0 to 2;

R¹ and R² are independently H, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl,heteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P and O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more halogen, OH, CN, —NO₂, oxo, —SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰,—S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R⁹, —C(O)OR⁹, —C(O)NR⁹R¹⁰, —NR⁹S(O)₂R¹⁰,—S(O)R⁹, —S(O)NR⁹R¹⁰, —NR⁹S(O)R⁹, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl,heterocycle, aryl, or heteroaryl; or

R¹ and R² together with the nitrogen to which they are attached can forma heterocyclyl or heteroaryl containing 1-5 heteroatoms selected fromthe group consisting of N, S, P and O, wherein the heterocyclyl orheteroaryl group is optionally substituted with one or more halogen, OH,CN, —NO₂, oxo, —SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰, —S(O)₂N(R⁹)₂—, —S(O)₂R⁹,—C(O)R⁹, —C(O)OR⁹, —C(O)NR⁹R¹⁰, —NR⁹S(O)₂R¹⁰, —S(O)R⁹, —S(O)NR⁹R¹⁰,—NR⁹S(O)R¹⁰, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl,C₃-C₈cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl;

R³ and R⁴ are independently halogen, OH, CN, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, or —C(O)NR⁹R¹⁰;

R⁵, R⁶, R⁷, and R⁸ are independently H, halogen, OH, CN, —NO₂,C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl,C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P and O, —SR⁹,—OR⁹, —NHR⁹, —NR⁹R¹⁰, —S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R⁹, —C(O)OR⁹,—NR⁹S(O)₂R¹⁰, —S(O)R⁹, —S(O)NR⁹R¹⁰, —NR⁸S(O)R⁹;

R⁹ and R¹⁰ are independently H, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, orheteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P and O

R¹¹ and R¹² are independently H, C₁-C₆alkyl, OH, NH₂, CN, or NO₂;

R¹³ is independently, at each occurrence, a bond, H, C₁-C₆alkyl,C₄-C₈cycloalkenyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroarylis optionally substituted with one or more R⁹;

R¹⁴ is independently, at each occurrence, H, C₁-C₆alkyl, orC₁-C₆haloalkyl; or

R⁶ and R¹⁴ together with the atoms to which they are attached maycombine to form, independently, at each occurrence, 5-to-6 memberedheterocyclyl, wherein each C₃-C₈ cycloalkyl, or heterocyclyl isoptionally substituted with one or more R¹⁹; or

R¹³ and R¹⁴ together with the atoms to which they are attached maycombine to form independently, at each occurrence, C₃-C₈ cycloalkyl,heterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selectedfrom the group consisting of N, S, P and O, wherein each heterocyclyl orheteroaryl is optionally substituted with one or more R¹⁹;

R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are independently, at each occurrence, H, OH,NH₂, or C₁-C₃ alkyl, wherein the alkyl is optionally substituted withone or more R¹⁹; and

R¹⁹ are independently, at each occurrence, H, OH, NH₂, oxo, C₁-C₆alkyl,C₁-C₆Hhaloalkyl, C₁-C₆alkoxy;

provided that:(1) when X is H, n is 1;(2) when X is a bond, O, or CR¹¹R¹², n is 2;(3) when n is 3, X is CR¹¹ or N;(4) when n is 4 X is C;(5) only one of Q or X is —NHC(O)NH— at the time,(6) R¹ and R² together with the nitrogen to which they are attached,cannot form a pyrrolidinyl;(7) when R¹ and R² are methyl, R³ and R⁴ are halogen, and R⁵ and R⁸ areH, Linker is not

(8) when R¹ and R² together with the nitrogen to which they are attachedform a piperidinyl, R³ and R⁴ are halogen, and R⁵ and R⁸ are H, Linkeris not

and(9) when R¹ and R², together with the nitrogen to which they areattached, form 3-aminopiperidin-1-yl, R³ and R⁴ are halogen, and R⁵, R⁶,R⁷, and R⁸ are H, Linker is not

In another aspect pharmaceutical compositions are provided comprising acompound as set forth above, or a stereoisomer, pharmaceuticallyacceptable salt or prodrug thereof, and a pharmaceutically acceptablecarrier, diluent or excipient. The pharmaceutical composition can beeffective for treating a disease or disorder associated with fluidretention or salt overload. The pharmaceutical compositions can comprisethe compounds of the present invention for use in treating diseasesdescribed herein. The compositions can contain at least one compound ofthe invention and a pharmaceutically acceptable carrier.

Another aspect of the invention relates a method for inhibitingNHE-mediated antiport of sodium and hydrogen ions. The method comprisesadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound or pharmaceutical composition described herein.

In another aspect, a method for treating a disorder associated withfluid retention or salt overload is provided. The method comprisesadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound or pharmaceutical composition as set forth above.

The present invention further provides compounds that can inhibitNHE-mediated antiport of sodium and hydrogen ions. The efficacy-safetyprofile of the compounds of the current invention can be improvedrelative to other known NHE-3 inhibitors. Additionally, the presenttechnology also has the advantage of being able to be used for a numberof different types of diseases, including, but not limited to, heartfailure (such as congestive heart failure), chronic kidney disease,end-stage renal disease, hypertension, essential hypertension, primaryhypertension, salt-sensitive hypertension, liver disease, and peroxisomeproliferator-activated receptor (PPAR) gamma agonist-induced fluidretention is provided, gastrointestinal motility disorder, irritablebowel syndrome, chronic constipation, chronic idiopathic constipation,chronic constipation occurring in cystic fibrosis patients, chronicconstipation occurring in chronic kidney disease patients,calcium-induced constipation in osteoporotic patients, opioid-inducedconstipation, a functional gastrointestinal tract disorder, Parkinson'sdisease, multiple sclerosis, gastroesophageal reflux disease, functionalheartburn, dyspepsia, functional dyspepsia, non-ulcer dyspepsia,gastroparesis, chronic intestinal pseudo-obstruction, Crohn's disease,ulcerative colitis and related diseases referred to as inflammatorybowel syndrome, colonic pseudo-obstruction, gastric ulcers, infectiousdiarrhea, cancer (colorectal), “leaky gut syndrome”, cystic fibrosisgastrointestinal disease, multi-organ failure, microscopic colitis,necrotizing enterocolitis, allergy—atopy, food allergy, infections(respiratory), acute inflammation (e.g., sepsis, systemic inflammatoryresponse syndrome), chronic inflammation (arthritis), obesity-inducedmetabolic diseases (e.g., nonalcoholic steatohepatitis, Type I diabetes,Type II diabetes, cardiovascular disease), kidney disease, diabetickidney disease, cirrhosis, nonalcoholic steatohepatitis, nonalcoholicfatty acid liver disease, Steatosis, primary sclerosing cholangitis,primary biliary cholangitis, portal hypertension, autoimmune disease(e.g., Type I diabetes, Celiac's Secondary PTH, ankylosing spondylitis,lupus, alopecia areata, rheumatoid arthritis, polymyalgia rheumatica,fibromyalgia, chronic fatigue syndrome, Sjogren's syndrome, vitiligo,thyroiditis, vasculitis, urticarial (hives), Raynaud's syndrome),Schizophrenia, autism spectrum disorders, hepatic encephlopathy, smallintestitinal bacterial overgrowth, and chronic alcoholism, secondaryhyperparathyroidism (PTH), celiac disease, hyperphosphatemia and thelike. Additional features and advantages of the present technology willbe apparent to one of skill in the art upon reading the DetailedDescription of the Invention, below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D: Depicts NHE3-independent changes in intracellular pH (pHi)modulate trans-epithelial electrical resistance in intestinal ileummonolayer cultures. Changes in pHi and trans-epithelial electricalresistance (TEER) with (FIG. 1A, FIG. 1B) nigericin and (FIG. 1C, FIG.1D) BAM 15 (3 μM) and FCCP (3 μM) compared with the known NHE3 inhibitortenapanor and vehicle (DMSO) control in monolayer cultures. *P<0.05,**P<0.01, ***P<0.001, ****P<0.0001 vs DMSO.

FIG. 2: Depicts dose-dependent reduction in urinary albumin excretion.

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the present invention relates to compounds of Formula

pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, ortautomer thereof, wherein: R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹⁵, R¹⁶,R¹⁷, R¹⁸, n, u, X, and Linker are described as herein.

The details of the invention are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. All patents and publications cited in thisspecification are incorporated herein by reference in their entireties.

Definitions

Unless the context requires otherwise, throughout the presentspecification and claims, the word “comprise” and variations thereof,such as, “comprises” and “comprising” are to be construed in an open,inclusive sense, that is as “including, but not limited to”.

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the present invention. Thus, the appearances of thephrases “in one embodiment” or “in an embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Imino” refers to the ═NH substituent.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

The term “substituted” used herein means any of the above groups (i.e.,alkyl, alkylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl)wherein at least one hydrogen atom is replaced by a bond to anon-hydrogen atoms such as, but not limited to: a halogen atom such asF, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups,alkoxy groups, and ester groups; a sulfur atom in groups such as thiolgroups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxidegroups; a nitrogen atom in groups such as amines, amides, alkylamines,dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides,imides, and enamines; a silicon atom in groups such as trialkylsilylgroups, dialkylarylsilyl groups, alkyldiarylsilyl groups, andtriarylsilyl groups; and other heteroatoms in various other groups.“Substituted” also means any of the above groups in which one or morehydrogen atoms are replaced by a higher-order bond (e.g., a double- ortriple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl,and ester groups; and nitrogen in groups such as imines, oximes,hydrazones, and nitriles. For example, “substituted” includes any of theabove groups in which one or more hydrogen atoms are replaced with—NR_(g)R_(h), —NR_(g)C(═O)R_(h), —NR_(g)C(═O)NR_(g)R_(h),—NR_(g)C(═O)OR_(h), —NR_(g)SO₂R_(h), —OC(═O)NR_(g)R_(h), —OR_(g),—SR_(g), —SOR_(g), —SO₂R_(g), —OSO₂R_(g), —SO₂OR_(g), ═NSO2R_(g), and—SO₂NR_(g)R_(h). “Substituted” also means any of the above groups inwhich one or more hydrogen atoms are replaced with —C(═O)R_(g),—C(═O)OR_(g), —C(═O)NR_(g)R_(h), —CH₂SO₂R_(g), —CH₂SO₂NR_(g)R_(h),—(CH₂CH₂O)₂₋₁₀R_(g). In the foregoing, R_(g) and R_(h) are the same ordifferent and independently hydrogen, alkyl, alkoxy, alkylamino,thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl,N-heteroaryl and/or heteroarylalkyl. “Substituted” further means any ofthe above groups in which one or more hydrogen atoms are replaced by abond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo,alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkylgroup. In addition, each of the foregoing substituents may also beoptionally substituted with one or more of the above substituents.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g. an alkyl group) can (but is not required to) bebonded other substituents (e.g. heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (i.e. a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bonded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds),having from one to twelve carbon atoms (C₁-C₁₂ alkyl), one to eightcarbon atoms (C₁-C₈ alkyl) or one to six carbon atoms (C₁-C₆ alkyl), andwhich is attached to the rest of the molecule by a single bond, e.g.,methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl,prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, ethynyl,propynyl, butynyl, pentynyl, hexynyl, and the like. Unless statedotherwise specifically in the specification, an alkyl group may beoptionally substituted.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined above containing one to twelve carbon atoms.Unless stated otherwise specifically in the specification, an alkoxygroup may be optionally substituted.

“Alkenyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkenyl” group contains at least onedouble bond in the chain. The double bond of an alkenyl group can beunconjugated or conjugated to another unsaturated group. Examples ofalkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl,pentenyl, or hexenyl. An alkenyl group can be unsubstituted orsubstituted. Alkenyl, as herein defined, may be straight or branched.

“Alkynyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkynyl” group contains at least onetriple bond in the chain. Examples of alkenyl groups include ethynyl,propanyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynyl groupcan be unsubstituted or substituted.

The term “cycloalkyl” means monocyclic or polycyclic saturated carbonrings containing 3-18 carbon atoms. Examples of cycloalkyl groupsinclude, without limitations, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl. A C₃-C₈ cycloalkyl is acycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkylgroup can be fused (e.g., decalin) or bridged (e.g., norbornane).

The term “cycloalkenyl” means monocyclic, non-aromatic unsaturatedcarbon rings containing 4-18 carbon atoms. Examples of cycloalkenylgroups include, without limitation, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, and norborenyl. A C₄-C₈ cycloalkenyl is acycloalkenyl group containing between 4 and 8 carbon atoms.

The terms “heterocyclyl” or “heterocycloalkyl” or “heterocycle” refer tomonocyclic or polycyclic 3 to 24-membered rings containing carbon andheteroatoms taken from oxygen, phosphorous, nitrogen, or sulfur andwherein there is not delocalized n electrons (aromaticity) shared amongthe ring carbon or heteroatoms. Heterocyclyl rings include, but are notlimited to, oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl,oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl,thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide,piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.A heteroycyclyl or heterocycloalkyl ring can also be fused or bridged,e.g., can be a bicyclic ring.

As used herein, the term “halo” or “halogen” means a fluoro, chloro,bromo, or iodo group.

The term “carbonyl” refers to a functional group composing a carbon atomdouble-bonded to an oxygen atom. It can be abbreviated herein as “oxo”,as C(O), or as C═O.

The term “aryl” refers to cyclic, aromatic hydrocarbon groups that have1 to 2 aromatic rings, including monocyclic or bicyclic groups such asphenyl, biphenyl or naphthyl. Where containing two aromatic rings(bicyclic, etc.), the aromatic rings of the aryl group may be joined ata single point (e.g., biphenyl), or fused (e.g., naphthyl). The arylgroup may be optionally substituted by one or more substituents, e.g., 1to 5 substituents, at any point of attachment. Exemplary substituentsinclude, but are not limited to, —H, -halogen, —O—C₁-C₆alkyl,—C₁-C₆alkyl, —OC₂-C₆alkenyl, —OC₂-C₆alkynyl, —C₂-C₆alkenyl,—C₂-C₆alkynyl, —OH, —OP(O)(OH)₂, —OC(O)C₁-C₆alkyl, —C(O)C₁-C₆alkyl,—OC(O)OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂,—S(O)₂—C₁-C₆alkyl, —S(O)NHC₁-C₆alkyl, and —S(O)N(C₁-C₆alkyl)₂. Thesubstituents can themselves be optionally substituted. Furthermore whencontaining two fused rings the aryl groups herein defined may have anunsaturated or partially saturated ring fused with a fully saturatedring. Exemplary ring systems of these aryl groups include indanyl,indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic aromatic radical or a polycyclic aromatic radical of 5 to 24ring atoms, containing one or more ring heteroatoms selected from N, S,P, and O, the remaining ring atoms being C. Heteroaryl as herein definedalso means a bicyclic heteroaromatic group wherein the heteroatom isselected from N, S, P, and O. The aromatic radical is optionallysubstituted independently with one or more substituents describedherein. Examples include, but are not limited to, furyl, thienyl,pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl,oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl,benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl,indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl,thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl,indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl,1,6-naphthyridinyl, benzo[de]isoquinolinyl,pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl,tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl,3,4-dihydro-2H-²-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene,pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl,1H-pyrido[3,4-b][1,4]thiazinyl, benzooxazolyl, benzoisoxazolyl,furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl,furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazol[1,2-a]pyrimidinyl,[1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl,benzo[cl][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one,3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl,and derivatives thereof. Furthermore when containing two fused rings theheteroaryl groups herein defined may have an unsaturated or partiallysaturated ring fused with a fully saturated ring. Exemplary ring systemsof these heteroaryl groups include indolinyl, indolinonyl,dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine,3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl,and dihydrobenzoxanyl.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound of the invention. Thus, the term “prodrug” refers to ametabolic precursor of a compound of the invention that ispharmaceutically acceptable. A prodrug may be inactive when administeredto a subject in need thereof, but is converted in vivo to an activecompound of the invention. Prodrugs are typically rapidly transformed invivo to yield the parent compound of the invention, for example, byhydrolysis in blood. The prodrug compound often offers advantages ofsolubility, tissue compatibility or delayed release in a mammalianorganism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24(Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi,T., et al., A.C.S. Symposium Series, Vol. 14, and in BioreversibleCarriers in Drug Design, Ed. Edward B. Roche, American PharmaceuticalAssociation and Pergamon Press, 1987.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound of the invention in vivowhen such prodrug is administered to a mammalian subject. Prodrugs of acompound of the invention may be prepared by modifying functional groupspresent in the compound of the invention in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compound of the invention. Prodrugs include compounds of theinvention wherein a hydroxy, amino or mercapto group is bonded to anygroup that, when the prodrug of the compound of the invention isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol or amide derivatives of amine functional groupsin the compounds of the invention and the like.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfrom, for example, the oxidation, reduction, hydrolysis, amidation,esterification, and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising administering a compound of thisinvention to a mammal for a period of time sufficient to yield ametabolic product thereof. Such products are typically identified byadministering a radiolabelled compound of the invention in a detectabledose to an animal, such as rat, mouse, guinea pig, monkey, or to human,allowing sufficient time for metabolism to occur, and isolating itsconversion products from the urine, blood or other biological samples.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol, 2dimethylaminoethanol, 2 diethylaminoethanol, dicyclohexylamine, lysine,arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine,benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine,theobromine, triethanolamine, tromethamine, purines, piperazine,piperidine, N ethylpiperidine, polyamine resins and the like.Particularly preferred organic bases are isopropylamine, diethylamine,ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention may be truesolvates, while in other cases, the compound of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centers and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R) or (S) or, as(D) or (L) for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R) and (S), or (D) and (L) isomersmay be prepared using chiral synthons or chiral reagents, or resolvedusing conventional techniques, for example, chromatography andfractional crystallization. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centres of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

In accordance with the present disclosure, the compounds describedherein are designed to be substantially active or localized in thegastrointestinal lumen of a human or animal subject. The term“gastrointestinal lumen” is used interchangeably herein with the term“lumen,” to refer to the space or cavity within a gastrointestinal tract(GI tract, which can also be referred to as the gut), delimited by theapical membrane of GI epithelial cells of the subject. In someembodiments, the compounds are not absorbed through the layer ofepithelial cells of the GI tract (also known as the GI epithelium).“Gastrointestinal mucosa” refers to the layer(s) of cells separating thegastrointestinal lumen from the rest of the body and includes gastricand intestinal mucosa, such as the mucosa of the small intestine. A“gastrointestinal epithelial cell” or a “gut epithelial cell” as usedherein refers to any epithelial cell on the surface of thegastrointestinal mucosa that faces the lumen of the gastrointestinaltract, including, for example, an epithelial cell of the stomach, anintestinal epithelial cell, a colonic epithelial cell, and the like.

A “subject” is a human, but can also be an animal in need of treatmentwith a compound of the disclosure, e.g., companion animals (e.g., dogs,cats, and the like), farm animals (e.g., cows, pigs, horses and thelike) and laboratory animals (e.g., rats, mice, guinea pigs and thelike).

“Substantially systemically non-bioavailable” and/or “substantiallyimpermeable” as used herein (as well as variations thereof) generallyrefer to situations in which a statistically significant amount, and insome embodiments essentially all of the compound of the presentdisclosure (which includes the NHE-inhibitor small molecule), remains inthe gastrointestinal lumen. For example, in accordance with one or moreembodiments of the present disclosure, at least about 70%, about 80%,about 90%, about 95%, about 98%, about 99%, or even about 99.5%, of thecompound remains in the gastrointestinal lumen. In such cases,localization to the gastrointestinal lumen refers to reducing netmovement across a gastrointestinal layer of epithelial cells, forexample, by way of both transcellular and paracellular transport, aswell as by active and/or passive transport. The compound in suchembodiments is hindered from net permeation of a layer ofgastrointestinal epithelial cells in transcellular transport, forexample, through an apical membrane of an epithelial cell of the smallintestine. The compound in these embodiments is also hindered from netpermeation through the “tight junctions” in paracellular transportbetween gastrointestinal epithelial cells lining the lumen.

In this regard it is to be noted that, in one particular embodiment, thecompound is essentially not absorbed at all by the GI tract orgastrointestinal lumen. As used herein, the terms “substantiallyimpermeable” or “substantially systemically non-bioavailable” refers toembodiments wherein no detectable amount of absorption or permeation orsystemic exposure of the compound is detected, using means generallyknown in the art.

In this regard it is to be further noted, however, that in alternativeembodiments “substantially impermeable” or “substantially systemicallynon-bioavailable” provides or allows for some limited absorption in theGI tract, and more particularly the gut epithelium, to occur (e.g., somedetectable amount of absorption, such as for example at least about0.1%, 0.5%, 1% or more and less than about 30%, 20%, 10%, 5%, etc., therange of absorption being for example between about 1% and 30%, or 5%and 20%, etc.; stated another way, “substantially impermeable” or“substantially systemically non-bioavailable” refers to compounds thatexhibit some detectable permeability to an epithelium layer of cells inthe GI tract of less than about 20% of the administered compound (e.g.,less than about 15%, about 10%, or even about 5%, and for examplegreater than about 0.5%, or 1%), but then are cleared by the liver(i.e., hepatic extraction) and/or the kidney (i.e., renal excretion).

In accordance with the present disclosure, and as further detailedherein below, it has been found that the inhibition of NHE-mediatedantiport of sodium ions (Na⁺) and hydrogen ions (H⁺) in thegastrointestinal tract, and more particularly the gastrointestinalepithelia, is a powerful approach to the treatment of various disordersthat may be associated with or caused by fluid retention and/or saltoverload, and/or disorders such as heart failure (in particular,congestive heart failure), chronic kidney disease, end-stage renaldisease, liver disease, and/or peroxisome proliferator-activatedreceptor (PPAR) gamma agonist-induced fluid retention. Morespecifically, it has been found that the inhibition of the NHE-mediatedantiport of sodium ions and hydrogen ions in the GI tract increases thefecal excretion of sodium, effectively reducing systemic levels ofsodium and fluid. This, in turn, improves the clinical status of apatient suffering from, for example, CHF, ESRD/CKD and/or liver disease.It has further been found that such a treatment may optionally beenhanced by the co-administration of other beneficial compounds orcompositions, such as for example a fluid-absorbing polymer. Thefluid-absorbing polymer may optimally be chosen so that it does notblock or otherwise negatively interfere with the mechanism of action ofthe co-dosed NHE-inhibiting compound.

Additionally, and also as further detailed herein below, it has furtherbeen found that the inhibition of NHE-mediated antiport of sodium ions(Na⁺) and hydrogen ions (H⁺) in the gastrointestinal tract, and moreparticularly the gastrointestinal epithelia, is a powerful approach tothe treatment of hypertension, that may be associated with or caused byfluid retention and/or salt overload. More specifically, it has beenfound that the inhibition of the NHE-mediated antiport of sodium ionsand hydrogen ions in the GI tract increases the fecal excretion ofsodium, effectively reducing systemic levels of sodium and fluid. This,in turn, improves the clinical status of a patient suffering fromhypertension. Such a treatment may optionally be enhanced by theco-administration of other beneficial compounds or compositions, such asfor example a fluid-absorbing polymer. The fluid-absorbing polymer mayoptimally be chosen so that it does not block or otherwise negativelyinterfere with the mechanism of action of the co-dosed NHE-inhibitingcompound.

Additionally, and also as further detailed herein below, it has furtherbeen found that the inhibition of NHE-mediated antiport of sodium ions(Na⁺) and hydrogen ions (H⁺) in the gastrointestinal tract, and moreparticularly the gastrointestinal epithelia, is a powerful approach tothe treatment of various gastrointestinal tract disorders, including thetreatment or reduction of pain associated with gastrointestinal tractdisorders, and more particularly to the restoration of appropriate fluidsecretion in the gut and the improvement of pathological conditionsencountered in constipation states. Applicants have further recognizedthat by blocking sodium ion re-absorption, the compounds of the presentdisclosure restore fluid homeostasis in the GI tract, particularly insituations wherein fluid secretion/absorption is altered in such a waythat it results in a high degree of feces dehydration, low gut motility,and/or a slow transit-time producing constipation states and GIdiscomfort generally. It has further been found that such a treatmentmay optionally be enhanced by the co-administration of other beneficialcompounds or compositions, such as for example a fluid-absorbingpolymer. The fluid-absorbing polymer may optimally be chosen so that itdoes not block or otherwise negatively interfere with the mechanism ofaction of the co-dosed NHE-inhibiting compound.

Due to the presence of NHEs in other organs or tissues in the body, themethod of the present disclosure employs the use of compounds andcompositions that are desirably highly selective or localized, thusacting substantially in the gastrointestinal tract without exposure toother tissues or organs. In this way, any systemic effects can beminimized (whether they are on-target or off-target). Accordingly, it isto be noted that, as used herein, and as further detailed elsewhereherein, “substantially active in the gastrointestinal tract” generallyrefers to compounds that are substantially systemically non-bioavailableand/or substantially impermeable to the layer of epithelial cells, andmore specifically epithelium of the GI tract. It is to be further notedthat, as used herein, and as further detailed elsewhere herein,“substantially impermeable” more particularly encompasses compounds thatare impermeable to the layer of epithelial cells, and more specificallythe gastrointestinal epithelium (or epithelial layer). “Gastrointestinalepithelium” refers to the membranous tissue covering the internalsurface of the gastrointestinal tract. Accordingly, by beingsubstantially impermeable, a compound has very limited ability to betransferred across the gastrointestinal epithelium, and thus contactother internal organs (e.g., the brain, heart, liver, etc.). The typicalmechanism by which a compound can be transferred across thegastrointestinal epithelium is by either transcellular transit (asubstance travels through the cell, mediated by either passive or activetransport passing through both the apical and basolateral membranes)and/or by paracellular transit, where a substance travels between cellsof an epithelium, usually through highly restrictive structures known as“tight junctions”.

Without wishing to be bound to any particular theory, it is believedthat the NHE-inhibiting compounds (e.g., NHE-3, -2 and/or -8 inhibitors)of the present disclosure are believed to act via a distinct and uniquemechanism, to decrease paracellular permeability of the intestine. NHE3is expressed at high levels on the apical surface of thegastrointestinal tract and couples luminal Na absorption to thesecretion of intracellular protons. Inhibition of NHE3, by theNHE-inhibiting compounds (e.g., NHE-3, -2 and/or -8 inhibitors) of thepresent disclosure, results in accumulation of intracellular protons.The intracellular proton retention accompanying NHE3 inhibitionmodulates the tight junction between cells to decrease paracellularpermeability which can be measured by an increase in transepithelialelectrical resistance. Since increased paracellular and/or transcellularpermeability of the intestine is observed in many diseases including,but not limited to a gastrointestinal motility disorder, irritable bowelsyndrome, chronic constipation, chronic idiopathic constipation, chronicconstipation occurring in cystic fibrosis patients, chronic constipationoccurring in chronic kidney disease patients, calcium-inducedconstipation in osteoporotic patients, opioid-induced constipation,multiple sclerosis-induced constipation, parkinson's disease-inducedconstipation, a functional gastrointestinal tract disorder,gastroesophageal reflux disease, functional heartburn, dyspepsia,functional dyspepsia, non-ulcer dyspepsia, gastroparesis, chronicintestinal pseudo-obstruction, Crohn's disease, ulcerative colitis andrelated diseases referred to as inflammatory bowel disease, colonicpseudo-obstruction, gastric ulcers, infectious diarrhea, cancer(colorectal), “leaky gut syndrome”, cystic fibrosis gastrointestinaldisease, multi-organ failure, microscopic colitis, necrotizingenterocolitis, allergy—atopy, food allergy, infections (respiratory),acute inflammation (e.g., sepsis, systemic inflammatory responsesyndrome), chronic inflammation (arthritis), obesity-induced metabolicdiseases (e.g., nonalcoholic steatohepatitis, Type I diabetes, Type IIdiabetes, cardiovascular disease), kidney disease, diabetic kidneydisease, cirrhosis, nonalcoholic steatohepatitis, nonalcoholic fattyacid liver disease, Steatosis, primary sclerosing cholangitis, primarybiliary cholangitis, portal hypertension, autoimmune disease (e.g., TypeI diabetes, ankylosing spondylitis, lupus, alopecia areata, rheumatoidarthritis, polymyalgia rheumatica, fibromyalgia, chronic fatiguesyndrome, Sjogren's syndrome, vitiligo, thyroiditis, vasculitis,urticarial (hives), Raynaud's syndrome), Schizophrenia, autism spectrumdisorders, hepatic encephlopathy, small intestinal bacterial overgrowth,and chronic alcoholism, and the like it is anticipated that NHEinhibition could provide therapeutic benefit in these diseases bydecreasing paracellular and/or transcellular permeability in theintestine

Thus in some embodiments, the present disclosure provides methods ofdecreasing paracellular permeability of the intestine. In someembodiments, the method of decreasing paracellular permeability of theintestine comprises administration of an NHE3 inhibitor. In someembodiments, the inhibition of NHE3 results in an accumulation ofintracellular protons. In some embodiments, the decrease in paracellularpermeability is due to an increase in intracellular protons independentof and without NHE3 inhibition. In other words, an increase inintracellular protons without NHE3 inhibition results in a decrease inparacelllar permeability. Thus methods of decreasing paracellularpermeability comprising increasing intracellular protons is provided. Insome embodiments, methods of treating diseases associated withparacellular permeability are provided comprising administering an agentthat increases intracellular protons at tight junctions therebydecreasing paracellular permeability and thus treating the disease. Nonlimiting examples of such diseases include, Crohn's disease, ulcerativecolitis and related diseases referred to as inflammatory bowel syndrome,colonic pseudo-obstruction, gastric ulcers, infectious diarrhea, cancer(colorectal), “leaky gut syndrome”, cystic fibrosis gastrointestinaldisease, multi-organ failure, microscopic colitis, necrotizingenterocolitis, allergy—atopy, food allergy, infections (respiratory),acute inflammation (e.g., sepsis, systemic inflammatory responsesyndrome), chronic inflammation (arthritis), obesity-induced metabolicdiseases (e.g., nonalcoholic steatohepatitis, Type I diabetes, Type IIdiabetes, cardiovascular disease), kidney disease, diabetic kidneydisease, cirrhosis, nonalcoholic steatohepatitis, nonalcoholic fattyacid liver disease, Steatosis, primary sclerosing cholangitis, primarybiliary cholangitis, portal hypertension, autoimmune disease (e.g., TypeI diabetes, ankylosing spondylitis, lupus, alopecia areata, rheumatoidarthritis, polymyalgia rheumatica, fibromyalgia, chronic fatiguesyndrome, Sjogren's syndrome, vitiligo, thyroiditis, vasculitis,urticarial (hives), Raynaud's syndrome), Schizophrenia, autism spectrumdisorders, hepatic encephlopathy, small intestinal bactreial overgrowth,and chronic alcoholism, and the like.

In some embodiments, the present disclosure provides methods ofmodulating transcellular permeability of the intestine. In someembodiments, the method of modulating transcellular permeability of theintestine comprises administration of an NH₄E3 inhibitor. In someembodiments, the inhibition of NHE3 results in a substance travellingthrough the cell, mediated by either passive or active transport passingthrough both the apical and basolateral membranes. Thus methods ofmodulating transcellular permeability comprising mediating eitherpassive or active transport of a substance passing through both theapical and basolateral membranes is provided. In some embodiments,methods of treating diseases associated with transcellular permeabilityare provided comprising administering an agent that mediates eitherpassive or active transport of a substance passing through both theapical and basolateral membranes of a cell, thereby modulatingtranscellular permeability and thus treating the disease. Non limitingexamples of such diseases include a gastrointestinal motility disorder,irritable bowel syndrome, chronic constipation, chronic idiopathicconstipation, chronic constipation occurring in cystic fibrosispatients, chronic constipation occurring in chronic kidney diseasepatients, calcium-induced constipation in osteoporotic patients,opioid-induced constipation, multiple sclerosis-induced constipation,parkinson's disease-induced constipation, a functional gastrointestinaltract disorder, gastroesophageal reflux disease, functional heartburn,dyspepsia, functional dyspepsia, non-ulcer dyspepsia, gastroparesis,chronic intestinal pseudo-obstruction.

The compounds of the present disclosure may therefore not be absorbed,and are thus essentially not systemically bioavailable at all (e.g.,impermeable to the gastrointestinal epithelium at all), or they show nodetectable concentration of the compound in serum. Alternatively, thecompounds may: (i) exhibit some detectable permeability to the layer ofepithelial cells, and more particularly the epithelium of the GI tract,of less than about 20% of the administered compound (e.g., less thanabout 15%, about 10%, or even about 5%, and for example greater thanabout 0.5%, or 1%), but then are rapidly cleared in the liver (i.e.,hepatic extraction) via first-pass metabolism; and/or (ii) exhibit somedetectable permeability to the layer of epithelial cells, and moreparticularly the epithelium of the GI tract, of less than about 20% ofthe administered compound (e.g., less than about 15%, about 10%, or evenabout 5%, and for example greater than about 0.5%, or 1%), but then arerapidly cleared in the kidney (i.e., renal excretion).

Compounds may also be cleared from circulation unchanged into the bileby biliary excretion. The compounds of the present disclosure maytherefore not exhibit detectable concentrations in the bile.Alternatively, the compounds may exhibit some detectable concentrationin the bile and more particularly the epithelium of the biliary tractand gallbladder of 10 μM, less than 1 μM, less than 0.1 μM, less than0.01 μM or less than about 0.001 μM.

In this regard it is to be still further noted that, as used herein,“substantially systemically non-bioavailable” generally refers to theinability to detect a compound in the systemic circulation of an animalor human following an oral dose of the compound. For a compound to bebioavailable, it must be transferred across the gastrointestinalepithelium (that is, substantially permeable as defined above), betransported via the portal circulation to the liver, avoid substantialmetabolism in the liver, and then be transferred into systemiccirculation.

Without being held to any particular theory, the NHE-inhibitingcompounds (e.g., NHE-3, -2 and/or -8 inhibitors) of the presentdisclosure are believed to act via a distinct and unique mechanism,causing the retention of fluid and ions in the GI tract (and stimulatingfecal excretion) rather than stimulating increased secretion of saidfluid and ions. For example, lubiprostone (Amitiza® Sucampo/Takeda) is abicyclic fatty acid prostaglandin E1 analog that activates the Type 2Chloride Channel (ClC-2) and increases chloride-rich fluid secretionfrom the serosal to the mucosal side of the GI tract (see, e.g.,Pharmacological Reviews for Amitiza®, NDA package). Linaclotide (MD-1100acetate, Microbia/Forest Labs) is a 14 amino acid peptide analogue of anendogenous hormone, guanylin, and indirectly activates the CysticFibrosis Transmembrane Conductance Regulator (CFTR) thereby inducingfluid and electrolyte secretion into the GI (see, e.g., Li et al., J.Exp. Med., vol. 202 (2005), pp. 975-986). The substantially impermeableNHE-inhibiting compounds of the present disclosure act to inhibit thereuptake of salt and fluid rather than promote secretion. Since the GItract processes about 9 liters of fluid and about 800 meq of Na eachday, it is anticipated that NHE inhibition could permit the removal ofsubstantial quantities of systemic fluid and sodium to resorb edema andresolve CHF symptoms.

I. Substantially Impermeable or Substantially SystemicallyNon-Bioavailable NHE-Inhibiting Compounds

In one aspect, the compounds of the present disclosure are generallyrepresented by Formula (I):

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,isomers, and tautomers thereof,

wherein:

Linker is —(CHR¹³)_(p)—Y[—(CH₂)_(r)]_(s)—Z—R¹³—(CH₂)_(t)—Z—;

W is independently, at each occurrence, S(O)₂, C(O), or —(CH₂)_(m)—;

Z is independently, at each occurrence, a bond, C(O), or —C(O)NH—;

Y is independently, at each occurrence, O, S, NH, N(C₁-C₃alkyl), or—C(O)NH—;

Q is a bond, NH, —C(O)NH—, —NHC(O)NH—, —NHC(O)N(CH₃)—, or—NHC(O)NH—(CHR¹³); m is an integer from 1 to 2; n is an integer from 1to 4;

r and p are independently, at each occurrence, integers from 0 to 8;

s is an integer from 0 to 4;

t is an integer from 0 to 4;

u is an integer from 0 to 2;

R¹ and R² are independently H, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl,heteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P and O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more halogen, OH, CN, —NO₂, oxo, —SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰,—S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R⁹, —C(O)OR⁹, —C(O)NR⁹R¹⁰, —NR⁹S(O)₂R¹⁰,—S(O)R⁹, —S(O)NR⁹R¹⁰, —NR⁹S(O)R⁹, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl,heterocycle, aryl, or heteroaryl; or

R¹ and R² together with the nitrogen to which they are attached can forma heterocyclyl or heteroaryl containing 1-5 heteroatoms selected fromthe group consisting of N, S, P and O, wherein the heterocyclyl orheteroaryl group is optionally substituted with one or more halogen, OH,CN, —NO₂, oxo, —SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰, —S(O)₂N(R⁹)₂—, —S(O)₂R⁹,—C(O)R⁹, —C(O)OR⁹, —C(O)NR⁹R¹⁰, —NR⁹S(O)₂R¹⁰, —S(O)R⁹, —S(O)NR⁹R¹⁰,—NR⁹S(O)R¹⁰, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl,C₃-C₈cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl;

R³ and R⁴ are independently halogen, OH, CN, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, or —C(O)NR⁹R¹⁰;

R⁵, R⁶, R⁷, and R⁸ are independently H, halogen, OH, CN, —NO₂,C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl,C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P and O, —SR⁹,—OR⁹, —NHR⁹, —NR⁹R¹⁰, —S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R⁹, —C(O)OR⁹,—NR⁹S(O)₂R¹⁰, —S(O)R⁹, —S(O)NR⁹R¹⁰, —NR⁸S(O)R⁹;

R⁹ and R¹⁰ are independently H, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, orheteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P and O

X is a bond, H, N, O, CR¹¹R¹², CR¹¹, C, —NHC(O)NH—, or C₃-C₆cyclolakyl;

R¹¹ and R¹² are independently H, C₁-C₆alkyl, OH, NH₂, CN, or NO₂;

R¹³ is independently, at each occurrence, a bond, H, C₁-C₆alkyl,C₄-C₈cycloalkenyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroarylis optionally substituted with one or more R¹⁹;

R¹⁴ is independently, at each occurrence, H, C₁-C₆alkyl, orC₁-C₆haloalkyl; or

R⁶ and R⁴ together with the atoms to which they are attached may combineto form, independently, at each occurrence, 5-to-6 memberedheterocyclyl, wherein each C₃-C₈ cycloalkyl, or heterocyclyl isoptionally substituted with one r more R¹⁹; or

R¹³ and R¹⁴ together with the atoms to which they are attached maycombine to form independently, at each occurrence, C₃-C₈ cycloalkyl,heterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selectedfrom the group consisting of N, S, P and O, wherein each heterocyclyl orheteroaryl is optionally substituted with one or more R¹⁹;

R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are independently, at each occurrence, H, OH,NH₂, or C₁-C₃ alkyl, wherein the alkyl is optionally substituted withone or more R¹⁹; and

R¹⁹ are independently, at each occurrence, H, OH, NH₂, oxo, C₁-C₆alkyl,C₁-C₆Hhaloalkyl, C₁-C₆alkoxy

provided that:

(1) when X is H, n is 1;

(2) when X is a bond, O, or CR¹¹R¹², n is 2;

(3) when n is 3, X is CR¹¹ or N;

(4) when n is 4 X is C;

(5) only one of Q or X is —NHC(O)NH— at the time,

(6) R¹ and R² together with the nitrogen to which they are attached,cannot form a pyrrolidinyl;

(7) when R¹ and R² are methyl, R³ and R⁴ are halogen, and R⁵ and R⁸ areH, Linker is not

(8) when R¹ and R² together with the nitrogen to which they are attachedform a piperidinyl, R³ and R⁴ are halogen, and R⁵ and R⁸ are H, Linkeris not

(9) when R¹ and R², together with the nitrogen to which they areattached, form 3-aminopiperidin-1-yl, R³ and R⁴ are halogen, and R⁵, R⁶,R⁷, and R⁸ are H, Linker is not

In an embodiment the NHE-inhibiting compounds of Formula (I) possessoverall physicochemical properties that render them substantiallyimpermeable or substantially systemically non-bioavailable.

In an embodiment, the compound of the invention has a structureaccording to formula I′

or a pharmaceutically acceptable salt thereof,

wherein:

Linker is —R¹³—(CHR¹³)_(p)—[Y—(CH₂)_(r)]_(s)—Z—R¹³—(CH₂)_(t)—Z—;

X is a bond, H, N, O, CR¹¹R¹², CR¹¹, C, —NHC(O)NH—, —(CHR¹³)_(p)— orC₃-C₆cyclolakyl;

W is independently, at each occurrence, S(O)₂, C(O), or —(CH₂)_(m)—;

Z is independently, at each occurrence, a bond, C(O), or —C(O)NH—;

Y is independently, at each occurrence, O, S, NH, N(C₁-C₃alkyl), or—C(O)NH—;

Q is a bond, NH, —C(O)NH—, —NHC(O)NH—, —NHC(O)N(CH₃)—, or—NHC(O)NH—(CHR¹³);

m is an integer from 1 to 2;

n is an integer from 1 to 4;

r and p are independently, at each occurrence, integers from 0 to 8;

s is an integer from 0 to 4;

t is an integer from 0 to 4;

u is an integer from 0 to 2;

R¹ and R² are independently H, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl,heteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P and O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more halogen, OH, CN, —NO₂, oxo, —SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰,—S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R⁹, —C(O)OR⁹, —C(O)NR⁹R¹⁰, —NR⁹S(O)₂R¹⁰,—S(O)R⁹, —S(O)NR⁹R¹⁰, —NR⁸S(O)R⁹, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl,heterocycle, aryl, or heteroaryl; or

R¹ and R² together with the nitrogen to which they are attached can forma heterocyclyl or heteroaryl containing 1-5 heteroatoms selected fromthe group consisting of N, S, P and O, wherein the heterocyclyl orheteroaryl group is optionally substituted with one or more halogen, OH,CN, —NO₂, oxo, —SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰, —S(O)₂N(R⁹)₂—, —S(O)₂R⁹,—C(O)R⁹, —C(O)OR⁹, —C(O)NR⁹R¹⁰, —NR⁹S(O)₂R¹⁰, —S(O)R⁹, —S(O)NR⁹R¹⁰,—NR⁹S(O)R¹⁰, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl,C₃-C₈cycloalkyl, heterocyclyl, heterocycle, aryl, or heteroaryl;

R³ and R⁴ are independently halogen, OH, CN, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, or —C(O)NR⁹R¹⁰;

R⁵, R⁶, R⁷, and R⁸ are independently H, halogen, OH, CN, —NO₂,C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl,C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P and O, —SR⁹,—OR⁹, —NHR⁹, —NR⁹R¹⁰, —S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R⁹, —C(O)OR⁹,—NR⁹S(O)₂R¹⁰, —S(O)R⁹, —S(O)NR⁹R¹⁰, —NR⁸S(O)R⁹;

R⁹ and R¹⁰ are independently H, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, orheteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P and O

R¹¹ and R¹² are independently H, C₁-C₆alkyl, OH, NH₂, CN, or NO₂;

R¹³ is independently, at each occurrence, a bond, H, C₁-C₆alkyl,C₄-C₈cycloalkenyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroarylis optionally substituted with one or more R¹⁹;

R¹⁴ is independently, at each occurrence, H, C₁-C₆alkyl, orC₁-C₆haloalkyl; or

R⁶ and R¹⁴ together with the atoms to which they are attached maycombine to form, independently, at each occurrence, 5-to-6 memberedheterocyclyl, wherein each C₃-C₈ cycloalkyl, or heterocyclyl isoptionally substituted with one or more R¹⁹; or

R¹³ and R¹⁴ together with the atoms to which they are attached maycombine to form independently, at each occurrence, C₃-C₈ cycloalkyl,heterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selectedfrom the group consisting of N, S, P and O, wherein each heterocyclyl orheteroaryl is optionally substituted with one or more R¹⁹;

R¹⁵, R¹⁶, R⁷, and R¹⁸ are independently, at each occurrence, H, OH, NH₂,or C₁-C₃ alkyl, wherein the alkyl is optionally substituted with one ormore R¹⁹; and

R¹⁹ are independently, at each occurrence, H, OH, NH₂, oxo, C₁-C₆alkyl,C₁-C₆Hhaloalkyl, C₁-C₆alkoxy.

It is to be noted that, in the many structures illustrated herein, allof the various linkages or bonds will not be shown in every instance.However, this should not be viewed in a limiting sense. Rather, it is tobe understood that the NHE-inhibiting molecule is bound orinterconnected in some way (e.g., by a bond or Linker) such that theresulting NHE-inhibiting compound is suitable for use (i.e.,substantially impermeable or substantially systemically non-bioavailablein the GI tract).

In yet other embodiments, the polyvalent NHE-inhibiting compound may bein oligomeric or polymeric form. It is to be noted that the repeat unitin each Formula (I) generally encompasses repeating units of variouspolymeric embodiments, including linear, branched and dendriticstructures, which may optionally be produced by methods referred toherein. In each polymeric, or more general polyvalent, embodiment, it isto be noted that each repeat unit may be the same or different, and mayor may not be linked through the “X” moiety by a Linker, which in turnmay be the same or different when present. In this regard it is to benoted that as used herein, “polyvalent” refers to a molecule that hasmultiple (e.g., 2, 4, 6, 8, 10 or more) NHE-inhibiting molecule.

In one embodiment of the invention, the Linker is-heterocyclyl-(CHR¹³)_(p)—[Y—(CH₂)_(r)]_(s)—. In another embodiment ofthe invention, the Linker may be represented by, but not limited to,

In another embodiment, the Linker may represented, without limitation,by

In some embodiments, of the invention, R¹ and R² are C₁-C₆alkyl. In someembodiments, R¹ and R² are methyl.

Yet in other embodiments of the compounds of Formula I, R¹ and R²together with the nitrogen to which they are attached may form aheterocyclyl or heteroaryl containing 1-5 heteroatoms selected from thegroup consisting of N, S, P and O. In some embodiments of the compoundsof Formula I, the heterocyclyl or heteroaryl formed by R¹ and R²together with the nitrogen to which they are attached is optionallysubstituted with one or more H, halogen, —NR⁹N¹⁰, or C₁-C₆alkyl.

In other embodiments of the compounds of Formula I, R¹ and R² togetherwith the nitrogen to which they are attached can form a heterocycle. Insome embodiments of the compounds of Formula I, the heterocycle formedby R¹ and R² together with the nitrogen to which they are attached isoptionally substituted with one or more oxo. In other embodiments of thecompounds of Formula I, R¹ and R² together with the nitrogen to whichthey are attached may also form a piperidine or piperazine. In furtherembodiments of the compounds of Formula I, the piperidine or piperazineis optionally substituted with one or more oxo, halogen, —NR⁹R¹⁰, orC₁-C₆alkyl. In a particular embodiment, the piperazine is substitutedwith methyl.

In some embodiments of the compounds of Formula I, R⁹ and R¹⁰ areC₁-C₆alkyl. In other embodiments, R⁹ and R¹⁰ are methyl. In someembodiments of the compounds of Formula I, R³ is halogen, CN,C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, or C₁-C₆haloalkoxy. In someembodiments of the compounds of Formula I, R³ is halogen, CN, orC₁-C₆alkyl. In an embodiment, R³ is CN. In some embodiments. R³ is F,Cl, CN, or methyl.

In some embodiments of the compounds of Formula I, R⁴ is halogen orC₁-C₆alkyl.

In some embodiments of the compounds of Formula I, R⁴ is F, Cl, ormethyl. In an embodiment, R³ is CN and R⁴ is C₁.

In other embodiments of the compounds of Formula I, R⁵ is H, halogen,C₁-C₆alkyl, or OR⁹. In yet other embodiments, R⁵ is 1-1, F, or methyl.

In another embodiment of the invention, R⁶, R⁷, and R⁸ are H, halogen,or C₁-C₆alkyl. In another embodiment, R⁶, R⁷, and R⁸ are all H. It hasbe observed that compounds of the invention incorporating a halogen oralkyl substituent at R⁶ while R⁵, R⁷ and R⁸ are each H exhibit lessinteraction with cytochrome enzymes. Accordingly, in an embodiment, R⁵,R⁷ and R⁸ are each H and R⁶ is halogen or C₁₋₆alkyl. In an embodiment,R⁵, R⁷ and R⁸ are each H and R⁶ is F. In an embodiment, R⁵, R⁷ and R⁸are each H and R⁶ is Me.

In another embodiment of the compounds of Formula I, Q is —NHC(O)NH—. Ina particular embodiment, Q is —NHC(O)NH— and the Linker is-heterocyclyl-(CHR¹³)_(p)—[Y—(CH₂)_(r)]_(s)—. In a particularembodiment, Q is —NHC(O)NH—, the Linker is-heterocyclyl-(CHR³)_(p)—[Y—(CH₂)_(r)]_(s)— and u is 0. In a particularembodiment, Q is —NHC(O)NH—, the Linker is-heterocyclyl-(CHR¹³)_(p)—[Y—(CH₂)_(r)]_(s)—, u is 0 and n is 2. In aparticular embodiment, Q is —NHC(O)NH—, the Linker is-heterocyclyl-(CHR¹³)_(p)—[Y—(CH₂)_(r)]_(s)—, u is 0, n is 2 and X is—(CHR¹³)_(p)— or C₃-C₆cyclolakyl. In another embodiment, Q is a bond.

In one embodiment of the compounds of Formula I, R¹⁵, R¹⁶, R¹⁷, and R¹⁸are all H. In one embodiment of the compounds of Formula I, R¹⁵ and R¹⁷are H. In one embodiment of the compounds of Formula I, R¹⁶ and R¹⁸ areOH. In yet another embodiment of the compounds of Formula I, R¹⁵ and R¹⁷are H and R¹⁶ and R^(1K) are OH.

In one embodiment of the compounds of Formula I, Y is O, r is 2, and sis 1. In another embodiment, Y is O, r is 2, and s is 2. In someembodiments, s is 0. In some embodiments, Z is C(O).

In some embodiments of the compounds of Formula I, R¹³ is H, C₁-C₆alkyl, heterocyclyl or heteroaryl. In some embodiments of the compoundsof Formula I, the heterocyclyl or heteroaryl of R is optionallysubstituted with one or more R¹⁹. In some embodiments, R¹³ isheterocyclyl optionally substituted with one or more R¹⁹. In someembodiments, R¹⁹ is oxo. In some embodiments of the compounds of FormulaI, n is 2. In other embodiments of the compounds of Formula I, n is 3 Or4.

In one embodiment of the invention, the compounds of Formula I have theFormula Ia or Ia′:

In one embodiment of the invention, the compounds of Formula I have theFormula Ib or Ib′:

wherein the ring Het represents R¹ and R² together with the nitrogen towhich they are attached can form a heterocyclyl or heteroaryl containing1-5 heteroatoms selected from the group consisting of N, S, P and O,wherein the heterocyclyl or heteroaryl group is optionally substitutedwith one or more halogen, OH, CN, —NO₂, oxo, —SR⁹, —OR⁹, —NHR⁹,—NR⁹R¹⁰), —S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R⁹, —C(O)OR⁹, —C(O)NR⁹R¹⁰,—NR⁹S(O)₂R¹⁰, —S(O)R⁹, —S(O)NR⁹R¹⁰, —NR⁹S(O)R¹⁰, C₁-C₆alkyl,C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl,heterocyclyl, heterocycle, aryl, or heteroaryl.

In one embodiment of the invention, the compounds of Formula I have theFormula Ic or Ic′:

wherein Het B represents a C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P and O, wherein each heterocyclyl or heteroaryl is optionallysubstituted with one or more R¹⁹.

In one embodiment of the invention, the compounds of Formula I have theFormula Id or Id′:

wherein Het is R¹³ which represents C₄-C₈cycloalkenyl, C₃-C₈cycloalkyl,heterocyclyl, aryl, or heteroaryl, wherein each cycloalkenyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R¹⁹.

In one embodiment of the invention, the compounds of Formula I have theFormula Ie or Ie′:

wherein the ring Het A represents R¹ and R² together with the nitrogento which they are attached can form a heterocyclyl or heteroarylcontaining 1-5 heteroatoms selected from the group consisting of N, S, Pand O, wherein the heterocyclyl or heteroaryl group is optionallysubstituted with one or more halogen, OH, CN, —NO₂, oxo, —SR⁹, —OR⁹,—NHR⁹, —NR⁹R¹⁰, —S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R⁹, —C(O)OR⁹, —C(O)NR⁹R¹⁰,—NR⁹S(O)₂R¹¹, —S(O)R⁹, —S(O)NR⁹R¹⁰, —NR⁹S(O)R¹⁰, C₁-C₆alkyl,C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl,heterocyclyl, heterocycle, aryl, or heteroaryl; and Het is R¹³ whichrepresents C₄-C₈cycloalkenyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each cycloalkenyl, cycloalkyl, heterocyclyl, aryl,or heteroaryl is optionally substituted with one or more R¹⁹.

In one embodiment of the invention, the compounds of Formula I have theFormula If or If′:

In one embodiment of the invention, the compounds of Formula I have theFormula

In one embodiment of the invention, the compounds of Formula I have theFormula Ih or Ih′:

wherein:Het represents R⁶ and R¹⁴ together with the atoms to which they areattached forming, independently, at each occurrence, a 5-to-6 memberedheterocyclyl.

In one embodiment of the invention, the compounds of Formula I have theFormula Ii or Ii′:

In other embodiments, compounds of Formula I include, but are notlimited to,1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea:

-   3-[2-(2-[2-[(4-[[(1S,2S)-2[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]    ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2    S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl    urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]benzene)    sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)    sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido    ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)    butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-(fluoro    benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea:-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]    ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   1-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)    butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methyl    benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)    ethyl] carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   1-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(tri    fluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]    ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methyl    benzene)sulfonamido]ethoxy]ethoxy)ethy]carbamoyl]amino)butyl]urea    dihydrochloride;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethyl]amino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-(fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]    carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]    carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl](carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,1S)-6-Chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-(fluorobenzene)sulfon    amido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-24    piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl(carbamoyl]amino)    butyl]urea;-   3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)    sulfonyl]    pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea;-   3-[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea;-   3-[(4-[[(3S)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea:-   3-[(4-[[(3R)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[4-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea;-   3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)    sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)    carbamoyl]amino]butyl)urea;-   3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;-   3-(2-[2-[(3S)-3-[[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-[[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;-   3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;-   1-([1-[2(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)    sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-3-[4-[[([1-[2-(2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)    ethyl]-1H-1,2,3-triazol-4-yl]methyl)carbamoyl]amino]butyl)urea;-   (2R,3R,4R,5S)—N¹,N⁶-Bis([1-[2-(2-[2-[(4-[[(1S,2)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-2,3,4,5-tetrahydroxyhexanediamide;-   3-[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)methyl]-1-[4-([[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)methyl]carbamoyl]amino)butyl]urea;-   3[(1-[6-(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]hexyl]-1H-1,2,3-triazol-4-yl)methyl]-1-[4-([[(1-[6-[(4-[[(1S,2S)-2-((3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]hexyl]-1H-1,2,3-triazol-4-yl)methyl(carbamoyl]amino)butyl]urea;-   (4R,4aS,8S,8aR)—N⁴,N⁸-Bis([1-(4-[4-((1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenyl    sulfonamide]butyl)-1H-1,2,3-triazol-4-yl(methyl)-2,2,6,6-tetramethyl-tetrahydro-[1,3]dioxino[5,4-d][1,3]dioxine-4,8-dicarboxamide;-   (4R,4aS,8S,8aR)—N⁴,N⁸-Bis([1-(6-[4-((1S,2S)-2-[(3R)-3-amino    piperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenylsulfonamido]hexyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-1-tetrahydro-[1,3]dioxino[5,4-d][[1,3]dioxine-4,8-dicarboxamide;-   3-[8-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)    sulfonamido]octyl]carbamoyl)amino]butyl]urea;-   3-[8-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)    sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea;-   3-[8-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)    sulfonamido]octyl]carbamoyl)amino]butyl]urea;-   3-[8-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,1S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)    sulfonamido]octyl]carbamoyl)amino]butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]    carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(2M-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2S)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy](ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[2-Azabicyclo[2.2.1]heptan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.1]heptan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   1-[2-(2-[2-[(4-[[(1S,2S)-2-[2-Azabicyclo[2.2.2]octan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.2]octan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyelo[3.2.1]octan-8-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy](benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[9-azabicyclo[3.2.1]octan-8-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   1-[2-(2-[2-[(4-[[(1S,2S)-2-[8-Azabicyclo[3.3.1]nonan-9-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.3.1]nonan-9-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-Acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-Acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   4-[(1S,2S)-4,6-dichloro-1-[4-1    (2-[2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[4-(dimethylcarbamoyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)    sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)ethoxy]ethoxy]ethyl)    sulfamoyl]phenoxy]-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperazine-1-carboxamide;-   4-[(1S,2 S)-4,6-dichloro-1-[4-[(2-[2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2    S)-4,6-dichloro-2-[4-(dimethylcarbamoyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)eth    oxy]ethoxy]ethyl)sulfamoyl]-2-methylphenoxy]-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperazine-1-carboxamide;-   3-[2-(2-[2-[(4[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)    sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethyl    benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;    hydrochloride;-   1-[2-(2-[2-[(3-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,4-dimethylbenzene)sulfonamido]ethoxy]ethoxy)    ethyl]-3[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)    sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]    carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;    hydrochloride;-   1-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-difluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-difluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl(oxy)-N-[26-(|4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3,5-difluorophenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]-3,5-difluorobenzenesulfonamide;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   1(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-3-[4-[[(2-[2[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;-   1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-3-[4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl(ethoxy]ethyl)carbamoyl]amino]butyl)urea;-   3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[[(3S)-1-[(4-[[(1S,2)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]piperidin-4-yl]oxy)ethoxy]ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]piperidin-4-yl]oxy)ethoxy]ethyl]carbamoyl)amino]butyl]urea;-   1-(2-[(2S)-2-[4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl-3-(4-([[2-[(2-[2-[(4-(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea;    hydrochloride;-   3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea;-   3-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)    sulfonamido]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea    dihydrochloride:-   3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea;-   1-[2-(2-[2-[(4-[[((3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-2-methylpropoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-2-methylpropoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;    hydrochloride;-   1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;-   4-([(1S,2S)-2-[(R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-2-[(R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl(oxy)-2-chlorophenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]-2-chlorobenzenesulfonamide;-   4-([(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide;    tetra(trifluoroacetate);-   4-([(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide;    tetra(trifluoroacetate);-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;    tetra(trifluoroacetate);-   4-([1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;    tetra(trifluoroacetate);-   4-[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(S)-2-([4-[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide;    tetra(trifluoroacetate);-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide;    tetra(trifluoroacetate);-   4-([(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-(∥4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)-3-fluorobenzenesulfonamide;    tetra(trifluoroacetate);-   4-([(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)-3-fluorobenzenesulfonamide;    tetra(trifluoroacetate);-   4-([(1S,2S)-6-Chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamide;    tetra(trifluoroacetate);-   4-([(1S,2S)-6-Chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamide;    tetra(trifluoroacetate);-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-[(2S,13S)-14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2,13-dimethyl-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl]pyrrolidin-3-yl]benzenesulfonamide;-   N¹,N¹⁴-bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;-   N¹,N¹⁴-bis(2-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;

N¹,N¹⁸-Bis(1-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)piperidin-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide;

-   4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide;-   -([(1S,2S)-6-Chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide]piperidin-1-yl)-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl]piperidin-4-yl)benzenesulfonamide;-   N¹,N¹⁸-Bis([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide;-   N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-1-[16-(4[([4-[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)carbamoyl]piperidin-1-yl)-5,12-dioxo-4,6,11,13-tetraazahexadecyl]piperidine-4-carboxamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20)-[(S)-3-([4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl    oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20)-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-1(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-1(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-1(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-[-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-1(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-2-oxopiperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)-2-oxopiperidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[2-(2-[2-(3-[(1r,4r)-4-(3-[2-(2-[2-([4-[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)ethoxy]ethoxy)ethyl]ureido)cyclohexyl]ureido)ethoxy]ethoxy)ethyl]benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(18-[(r)-3-([4-([(1S,1S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide;-   N-(2-[2-(2-Aminoethoxy)ethoxy]ethyl)-4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide;-   N-[1-(4-Aminobutanoyl)piperidin-4-yl]-4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-(3-oxo-7,10-dioxa-2,4-diazadodecan-12-yl)benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-(1-[4-(3-methylureido)butanoyl]piperidin-4-yl)benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-yl]benzenesulfonamide;-   4-([4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-yl]piperidine-1-carboxamide;-   4-(3-[4-([4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-4-oxobutyl]ureido)-N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)butanamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(4-[3-(4-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-4-oxobutyl)ureido]butanoyl)piperidin-4-yl]benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[19-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecyl]benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-amido-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-amido-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide;-   4-([(1S,2S)-4-Cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-4-cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide;-   1,1′-(Butane-1,4-diyl)bis[3-(4-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinolin-2(1H)-yl]-4-oxobutyl)urea],-   1,1′-(Butane-1,4-diyl)bis[3-(4-[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinolin-2(1H)-yl]-4-oxobutyl)urea];-   N,N′-(6,14-Dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide];-   N,N-(6,14-Dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide];-   4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(18-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(18-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-f    (R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide;-   4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide;-   N¹,N¹⁴-Bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide,-   4-([(1S,2S)-6-Chloro-4-cyano-2-1    (R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-1    (R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)piperidin-4-yl]benzenesulfonamide;-   4-([(1S,2S)-4,6-Dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;-   N¹,N¹⁴-Bis(2-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide:-   1,1′-(Butane-1,4-diyl)bis(3-[2-(2-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindolin-2-yl]ethoxy)ethyl]urea);    and-   1,1′-(Butane-1,4-diyl)bis(3[I2-(2-[5-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindolin-2-yl]ethoxy)ethyl]urea).-   (1S,2S)-1-(4-{[(3S)-1-[2-(2-{[(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-4-carboxy-6-chloro-2-    [(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzenesulfonamido)-1-hydroxy-1λ⁴-Pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino}butyl)carbamoyl]amino}ethoxy)ethyl]-1-hydroxy-1λ⁴-pyrrolidin-3-yl]sulfamoyl}phenoxy)-6-chloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-indene-4-carboxylic    acid;-   3-(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}(2,3,5,6-²H₄)benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-({[(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}(2,3,5,6-²H₄)benzenesulfonamido)pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino}(1,1,2,2,3,3,4,4-²H₈)butyl)urea;-   3-(2-{2-[2-(4-{[(1S,2S)-4-cyano-6-methyl-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1    S,2    S)-4-cyano-6-methyl-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea;-   3-(2-{2-[(3S)-3-[4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-({[(2-[2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)urea;-   N-{2-[(3S)-3-[4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}/benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}-2-({[4-({[({(2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}carbamoyl)methyl]carbamoyl]amino)butyl]carbamoyl}    amino)acetamide;-   3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-[(1    s,4s)-4-{[(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}cyclohexyl]urea:-   1,3-bis(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)urea;-   4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-ident-1-yl]oxy)-N-[19-([4-([1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecyl]benzenesulfonamide;-   3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-1(1r,4r)-4-{[(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}cyclohexyl]urea;-   3-(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}(1,1,2,2,3,3,4,4-²H₈)butyl)urea;-   3-{4-[(3S)-3-[4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-4-oxobutyl}-1-{4-[({4-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy})    benzenesulfonamido)pyrrolidin-1-yl]-4-oxobutyl}carbamoyl)amino]butyl}urea;-   3-{4-[4-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzenesulfonamido)piperidin-1-yl]-4-oxobutyl}-1-{4-[({4-[4-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)piperidin-1-yl]-4-oxobutyl}carbamoyl)amino]butyl}urea;-   N-{2-[(3R)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}-2-({[4-({[({2-[(3R)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}carbamoyl)methyl]carbamoyl}amino)butyl]carbamoyl}amino)acetamide;-   3-(2-{2-[4-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)piperidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[4-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)piperidin-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)urea;-   3-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}-1-{4-[({2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}carbamoyl)amino]butyl}    urea; and-   (3S)—N-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonyl)-1-[2-(2-{[(4-{[(2-{2-[(3S)-3-[(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonyl)carbamoyl]pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)carbamoyl]amino}ethoxy)ethyl]pyrrolidine-3-carboxamide.

In other embodiments, W is S(O)₂, C(O), or —(CH₂)_(m)—. In otherembodiments, W is S(O)₂. In other embodiments, W is C(O). In otherembodiments, W is —(CH₂)₂—. In other embodiments, W is —(CH₂)—.

In some embodiments, Y is O, S, NH, N(C₁-C₃alkyl), or —C(O)NH—. In someembodiments, Y is O. In some embodiments, Y is S. In some embodiments, Yis NH. In some embodiments, Y is N(C₁-C₆alkyl). In some embodiments, Yis —C(O)NH—. In some embodiments, Y is O, S, NH, or N(C₁-C₃alkyl). Insome embodiments, Y is O, S, or NIH. In some embodiments, Y is O or S.

In some embodiments, Q is a bond, NH, —C(O)NH—, —NHC(O)NH—,—NHC(O)N(CH₃)—, or —NHC(O)NH—(CHR¹³). In some embodiments, Q is a bond,NH, —C(O)NH—, —NHC(O)NH—, or —NHC(O)N(CH₃)—. In some embodiments, Q is abond, NH, —C(O)NH—, or —NHC(O)NH—. In some embodiments, Q is a bond, NH,or —C(O)NH—. In some embodiments, Q is a bond or NH. In someembodiments, Q is a bond. In some embodiments, Q is —NHC(O)NH—. In someembodiments, Q is —C(O)NH—. In some embodiments, Q is —NHC(O)NH—. Insome embodiments, Q is —NHC(O)N(CH₃)—. In some embodiments, Q is—NHC(O)NH—(CHR¹³).

In some embodiments, R¹ and R² are independently H, C₁-C₆alkyl,C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl,heterocyclyl, aryl, or heteroaryl. In some embodiments, R¹ and R² areindependently H, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl,C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl, or aryl. In someembodiments, R¹ and R² are independently H, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, or heterocyclyl. Insome embodiments, R¹ and R² are independently H, C₁-C₆alkyl,C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl,heterocyclyl, aryl, or heteroaryl. In some embodiments, R¹ and R² areindependently H, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl,C₂-C₆alkynyl, or C₃-C₈cycloalkyl. In some embodiments, R¹ and R² areindependently H, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, orC₂-C₆alkynyl. In some embodiments, R¹ and R² are independently H,C₁-C₆alkyl, C₂-C₆alkenyl, or C₄-C₈cycloalkenyl. In some embodiments, R¹and R² are independently H, C₁-C₆alkyl, or C₂-C₆alkenyl. In someembodiments, R¹ and R² are independently H or C₁-C₆alkyl. In someembodiments, R¹ and R² are independently H, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, orheteroaryl wherein each alkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more halogen, OH, CN, —NO₂, oxo, —SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰,—S(O)₂N(R⁹)₂—, —S(O)₂R⁹, C(O)R⁹, —C(O)OR⁹, —C(O)NR⁹R¹⁰, —NR⁹S(O)₂R¹⁰,—S(O)R⁹, —S(O)NR⁹R¹⁰, —NRRS(O)R⁹, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl,heterocycle, aryl, or heteroaryl.

In another embodiment, R³ is halogen, OH, CN, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, or —C(O)NR⁹R¹⁰. In one embodiment, R³is halogen, OH, CN, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, orC₁-C₆haloalkoxy. In one embodiment, R³ is halogen, OH, CN, C₁-C₆alkyl,C₁-C₆alkoxy, or C₁-C₆haloalkyl. In one embodiment, R³ is halogen, OH,CN, C₁-C₆alkyl, or C₁-C₆alkoxy. In one embodiment, R³ is halogen, OH,CN, or C₁-C₆alkyl. R³ is halogen, OH, or CN. In one embodiment, R³ ishalogen or OH. In one embodiment, R³ is halogen. R³ is OH. In oneembodiment, R³ is CN. In one embodiment, R³ is C₁-C₆alkyl. In oneembodiment, R³ is C₁-C₆alkoxy. In one embodiment, R³ is C₁-C₆haloalkyl.In one embodiment, R³ is C₁-C₆haloalkoxy. In one embodiment, R⁴ is—C(O)NR⁹R¹⁰.

In another embodiment, R⁴ is halogen, OH, CN, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, C₁-C₆haloalkoxy, or —C(O)NR⁹R¹⁰. In one embodiment, R⁴is halogen, OH, CN, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, orC₁-C₆haloalkoxy. In one embodiment, R⁴ is halogen, OH, CN, C₁-C₆alkyl,C₁-C₆alkoxy, or C₁-C₆haloalkyl. In one embodiment, R⁴ is halogen, OH,CN, C₁-C₆alkyl, or C₁-C₆alkoxy. In one embodiment, R⁴ is halogen, OH,CN, or C₁-C₆alkyl. R³ is halogen, OH, or CN. In one embodiment, R⁴ ishalogen or OH. In one embodiment, R⁴ is halogen. R³ is OH. In oneembodiment, R⁴ is CN. In one embodiment, R⁴ is C₁-C₆alkyl. In oneembodiment, R⁴ is C₁-C₆alkoxy. In one embodiment, R⁴ is C₁-C₆haloalkyl,In one embodiment, R⁴ is C₁-C₆haloalkoxy. In one embodiment, R⁴ is—C(O)NR⁹R¹⁰.

In one embodiment, R⁵, R⁶, R⁷, and R⁸ are independently H, halogen, OH,CN, —NO₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl,C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P and O, —SR⁹,—OR⁹, —NHR⁹, —NR⁹R¹⁰, —S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R⁹, —C(O)OR¹⁰,—NR⁹S(O)₂R¹⁰, —S(O)R⁹, —S(O)NR⁹R¹⁰, —NR⁸S(O)R⁹. In one embodiment, R⁵,R⁶, R⁷, and R⁸ are independently H, halogen, OH, CN, —NO₂, C₁-C₆alkyl,C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl,heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected fromthe group consisting of N, S, P and O, —SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰,—S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R¹⁰, —C(O)OR⁹, —NR⁹S(O)₂R¹⁰, —S(O)R⁹,—S(O)NR⁹R¹⁰. In one embodiment, R⁵, R⁶, R⁷, and Rx are independently H,halogen, OH, CN, —NO₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl,C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing1-5 heteroatoms selected from the group consisting of N, S, P and O,—SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰, —S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R⁹, —C(O)OR⁹,—NR⁹S(O)₂. In one embodiment, R¹⁰. R⁵, R⁶, R⁷, and Rx are independentlyH, halogen, OH, CN, —NO₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl,C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing1-5 heteroatoms selected from the group consisting of N, S, P and O,—SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰,—S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R⁹, —C(O)OR⁹.In one embodiment, R⁵, R⁶, R⁷, and Rx are independently H, halogen, OH,CN, —NO₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl,C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P and O, —SR⁹,—OR⁹, —NHR⁹, —NR⁹R¹⁰, —S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R⁹. In oneembodiment, R⁵, R⁶, R⁷, and Rx are independently H, halogen, OH, CN,—NO₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl,C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P and O, —SR⁹,—OR⁹, —NHR⁹, —NR⁹R¹⁰, —S(O)₂N(R⁹)₂—, —S(O)₂R⁹. In one embodiment, R⁵,R⁶, R⁷, and Rx are independently H, halogen, OH, CN, —NO₂, C₁-C₆alkyl,C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl,heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected fromthe group consisting of N, S, P and O, —SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰,—S(O)₂N(R⁹)₂—. In one embodiment, R⁵, R⁶, R⁷, and R⁸ are independentlyH, halogen, OH, CN, —NO₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl,C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing1-5 heteroatoms selected from the group consisting of N, S, P and O,—SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰. In one embodiment, R⁵, R⁶, R⁷, and R⁸ areindependently H, halogen, OH, CN, —NO₂, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl,heteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P and O, —SR⁹, —OR⁹, —NHR⁹. In one embodiment, R⁵, R⁶, R⁷, andR⁸ are independently H, halogen, OH, CN, —NO₂, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl,heteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P and O, —SR⁹, —OR⁹. In one embodiment, R⁵, R⁶, R⁷, and R⁸ areindependently 11, halogen, OH, CN, —NO₂, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl,heteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P and O, —SR⁹. In one embodiment, R⁵, R⁶, R⁷, and R⁸ areindependently H, halogen, OH, CN, —NO₂, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, orheteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P and O. In one embodiment, R⁵, R⁶, R⁷, and R⁸ areindependently 11, halogen, OH, CN, —NO₂, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl, or aryl.In one embodiment, R⁵, R⁶, R⁷, and R⁸ are independently H, halogen, OH,CN, —NO₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl,C₃-C₈cycloalkyl, or heterocyclyl. In one embodiment, R⁵, R⁶, R⁷, and R⁸are independently H, halogen, OH, CN, —NO₂, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, or C₃-C₈cycloalkyl. In one embodiment,R⁵, R⁶, R⁷, and R⁸ are independently H, halogen, OH, CN, —NO₂,C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl, or C₂-C₆alkynyl. In oneembodiment, R⁵, R⁶, R⁷, and R⁸ are independently H, halogen, OH, CN,—NO₂, C₁-C₆alkyl, C₂-C₆alkenyl, or C₄-C₈cycloalkenyl. In one embodiment,R⁵, R⁶, R⁷, and R⁸ are independently H, halogen, OH, CN, —NO₂,C₁-C₆alkyl, or C₂-C₆alkenyl. In one embodiment, R⁵, R⁶, R⁷, and R⁸ areindependently H, halogen, OH, CN, —NO₂, or C₁-C₆alkyl. In oneembodiment, R⁵, R⁶, R⁷, and R⁸ are independently H, halogen, OH, CN,or—NO₂. In one embodiment, R⁵, R⁶, R⁷, and R⁸ are independently H,halogen, OH, or CN. In one embodiment, R⁵, R⁶, R⁷, and R⁸ areindependently H, halogen, or OH. In one embodiment, R⁵, R⁶, R⁷, and R⁸are independently H or halogen.

In one embodiment, R⁵, R¹⁶, R¹⁷, and R¹⁸ are independently, at eachoccurrence, H, OH, NH₂, or C₁-C₃ alkyl. In a further embodiment, R¹⁵,R¹⁶, R¹⁷, and R¹⁸ are independently, at each occurrence, H, OH, or NH₂.In a further embodiment, R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are independently, ateach occurrence, H or OH. In a further embodiment, R¹⁶, R¹⁷, and R¹⁸ areindependently, at each occurrence, H, OH, NH₂, or C₁-C₃ alkyl, whereinthe alkyl is optionally substituted with one or more R¹⁹.

In one embodiment, X is a bond, H, N, O, CR¹¹R¹², CR¹¹, C, —NIC(O)NH—,or C₃-C₆cyclolalkyl. In one embodiment, X is a bond, H, N, O, CR¹¹R¹²,CR¹¹, C, or —NHC(O)NH—. In one embodiment, X is a bond, H, N, O,CR¹¹R¹², CR¹¹, or C. In one embodiment, X is a bond, H, N, O, CR¹¹R¹²,or CR¹¹. In one embodiment, X is a bond, H, N, O, or CR¹¹R¹². In oneembodiment, X is a bond, H, N, or O. X is a bond, H, or N. In oneembodiment, X is a bond or H. in one embodiment, X is a bond. In anotherembodiment X is H and n is 1. In another embodiment, X is N when n is 3.In another embodiment, X is O and n is 2. In another embodiment, X isCR¹¹R¹² and n is 2. In another embodiment, X is CR¹¹ and n is 3. Inanother embodiment, X is C and n is 4. In another embodiment, X is—NHC(O)NH—. In another embodiment, X is C₃-C₆cyclolalkyl.

In some embodiments, R⁴ is H, C₁-C₆alkyl, or C₁-C₆haloalkyl. In someembodiments, R⁴ is H or C₁-C₆alkyl. In some embodiments, R¹⁴ is H. Insome embodiments, R¹⁴ is C₁-C₆alkyl. In some embodiments, R¹⁴ isC₁-C₆haloalkyl.

In yet other embodiments, R⁶ and R¹⁴ together with the atoms to whichthey are attached may combine to form, a 5-to-6 membered heterocyclyl.In other embodiments, R⁶ and R¹⁴ together with the atoms to which theyare attached may combine to form, independently, at each occurrence,5-to-6 membered heterocyclyl, wherein the heterocyclyl is optionallysubstituted with one or more R¹⁹.

In other embodiments, R¹³ and R¹⁴ together with the atoms to which theyare attached may combine to form independently, at each occurrence,C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl. In otherembodiments, R¹³ and R¹⁴ together with the atoms to which they areattached may combine to form independently, at each occurrence, C₃-C₈cycloalkyl, heterocyclyl, or aryl. In some embodiments, R¹³ and R¹⁴together with the atoms to which they are attached may combine to formindependently, at each occurrence, C₃-C₈ cycloalkyl or heterocyclyl. Insome embodiments, R¹³ and R¹⁴ together with the atoms to which they areattached may combine to form independently, at each occurrence, C₃-C₈cycloalkyl. In some embodiments, R¹³ and R¹⁴ together with the atoms towhich they are attached may combine to form independently, at eachoccurrence, heterocyclyl. In some embodiments, R¹³ and R¹⁴ together withthe atoms to which they are attached may combine to form independently,at each occurrence, aryl. In some embodiments, R¹³ and R¹⁴ together withthe atoms to which they are attached may combine to form independently,at each occurrence, heteroaryl.

In other embodiments, R¹³ and R¹⁴ together with the atoms to which theyare attached may combine to form independently, at each occurrence,C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein eachheterocyclyl or heteroaryl is optionally substituted with one or moreR¹⁹. In other embodiments, R¹³ and R¹⁴ together with the atoms to whichthey are attached may combine to form independently, at each occurrence,C₃-C₈ cycloalkyl, heterocyclyl, or aryl, wherein each heterocyclyl isoptionally substituted with one or more R¹⁹. In some embodiments, R¹³and R¹⁴ together with the atoms to which they are attached may combineto form independently, at each occurrence, C₃-C₈ cycloalkyl orheterocyclyl, wherein each heterocyclyl is optionally substituted withone or more R¹⁹. In some embodiments, R¹³ and R¹⁴ together with theatoms to which they are attached may combine to form independently, ateach occurrence, C₃-C₈ cycloalkyl. In some embodiments, R¹³ and R¹⁴together with the atoms to which they are attached may combine to formindependently, at each occurrence, heterocyclyl, wherein eachheterocyclyl is optionally substituted with one or more R¹¹. In someembodiments, R¹³ and R¹⁴ together with the atoms to which they areattached may combine to form independently, at each occurrence, aryl. Insome embodiments, R¹³ and R¹⁴ together with the atoms to which they areattached may combine to form independently, at each occurrence,heteroaryl, wherein each heteroaryl is optionally substituted with oneor more R¹⁹.

In some embodiments, u is 0, 1, or 2. In some embodiments, u is 0 or 1.In some embodiments, u is 0. In some embodiments, u is 1. In someembodiments, u is 2.

In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2,or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. Insome embodiments, n is 2. In some embodiments, n is 3. In someembodiments, n is 4.

In some embodiments, s is 0, 1, 2, 3, or 4. In some embodiments, s is 0,1, 2, or 3. In some embodiments, s is 0, 1, or 2. In some embodiments, sis 0 or 1. In some embodiments, s is 0. In some embodiments, s is 1. Insome embodiments, s is 2. In some embodiments, s is 3. In someembodiments, s is 4.

In some embodiments, r is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In someembodiments, r is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, r is0, 1, 2, 3, 4, 5, or 6. In some embodiments, r is 0, 1, 2, 3, 4, or 5.In some embodiments, r is 0, 1, 2, 3, or 4. In some embodiments, r is 0,1, 2, or 3. In some embodiments, r is 0, 1, or 2. In some embodiments, ris 0 or 1. In some embodiments, r is 0. In some embodiments, r is 1. Insome embodiments, r is 2. In some embodiments, r is 3. In someembodiments, r is 4. In some embodiments, r is 5. In some embodiments, ris 6. In some embodiments, r is 7. In some embodiments, r is 8.

In some embodiments, p is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In someembodiments, p is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, p is0, 1, 2, 3, 4, 5, or 6. In some embodiments, p is 0, 1, 2, 3, 4, or 5.In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0,1, 2, or 3. In some embodiments, p is 0, 1, or 2. In some embodiments, pis 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. Insome embodiments, p is 2. In some embodiments, p is 3. In someembodiments, p is 4. In some embodiments, p is 5. In some embodiments, pis 6. In some embodiments, p is 7. In some embodiments, p is 8.

In designing and making the substantially impermeable or substantiallysystemically non-bioavailable NHE-inhibiting compounds of the presentinvention that may be utilized for the treatments detailed in theinstant disclosure.

Another aspect, compounds of the present invention with extendedhydrocarbon functionalities may collapse upon themselves in anintramolecular fashion, causing an increased enthalpic barrier forinteraction with the desired biological target. Accordingly, whendesigning “X” and Linkers moieties, these are designed to be resistantto hydrophobic collapse. For example, conformational constraints such asrigid monocyclic, bicyclic or polycyclic rings can be installed in a “X”and Linker moiety to increase the rigidity of the structure. Unsaturatedbonds, such as alkenes and alkynes, may also or alternatively beinstalled. Such modifications may ensure the NHE-inhibiting compound isaccessible for productive binding with its target. Furthermore, thehydrophilicity of the Linkers may be improved by adding hydrogen bonddonor or acceptor motifs, or ionic motifs such as amines that areprotonated in the GI, or acids that are deprotonated. Such modificationswill increase the hydrophilicity of the “X” and Linker moieties and helpprevent hydrophobic collapse. Furthermore, such modifications will alsocontribute to the impermeability of the resulting compounds byincreasing tPSA.

One skilled in the art may also consider a variety of functional groupsthat will allow the facile and specific attachment of the rest of themolecule of the compounds of Formula I to the “X” moiety and/or Linker.These functional groups can include electrophiles, which can react withnucleophilic groups, and/or nucleophiles, which can react withelectrophilic “X” and Linker moieties. NHE-inhibiting compounds ofFormula I may also be similarly derivatized with, for example, boronicacid groups. The NHE-inhibiting compounds of Formula I may also containolefins via olefin metathesis chemistry, or alkynes or azides which canthen react with appropriate other “X” and Linker via [2+3]cycloaddition.

It is to be noted that one skilled in the art can envision a number of“X” and Linker moieties that may be functionalized with an appropriateelectrophile or nucleophile. Shown below are a series of such compoundsselected based on several design considerations, including solubility,steric effects, and their ability to confer, or be consistent with,favorable structure-activity relationships. In this regard it is to befurther noted, however, that the structures provided below, and above,are for illustration purposes only, and therefore should not be viewedin a limiting sense.

Exemplary electrophilic and nucleophilic Linker moieties include, butare not limited to, the Linker moieties illustrated in the Examples andthe following:

The linking moiety, Linker, in each of the described embodiments canalso be a chemical bond or other moiety, for example that can behydrophilic and/or hydrophobic. In one embodiment, the linking moietycan be a polymer moiety grafted onto a polymer backbone, for example,using living free radical polymerization approaches known in the art.

In another embodiment, “X” moieties illustrated in the compounds ofFormula I may also include, but are not limited to, ether moieties,ester moieties, sulfide moieties, disulfide moieties, amine moieties,aryl moieties, alkoxy]moieties, etc., such as, for example, thefollowing:

wherein the broken bonds (i.e., those having a wavy bond,

, through them) are points of connection to the rest of the molecule ofFormula I when n>1, where said points of connection can be made usingchemistries and functional groups known to the art of medicinalchemistry; and further wherein each p′, q′, r′ and s′ is anindependently selected integer ranging from about 0 to about 48, fromabout 0 to about 36, or from about 0 to about 24, or from about 0 toabout 16. In some instances, each p, q, r and s can be an independentlyselected integer ranging from about 0 to 12. Additionally, R′ can be asubstituent moiety generally selected from halide, hydroxyl, amine,thiol, ether, carbonyl, carboxyl, ester, amide, carbocyclic,heterocyclic, and moieties comprising combinations thereof.

In another approach, the “X” moiety of formula I may be a dendrimer,defined as a repeatedly branched molecule (see, e.g., J. M. J. Fréchet,D. A. Tomalia, Dendrimers and Other Dendritic Polymers, John Wiley &Sons, Ltd. NY, NY, 2001) and schematically represented below:

In this approach, the rest of the NHE-inhibiting molecule is attachedthrough Linker to one, several or optionally all termini located at theperiphery of the dendrimer. In another approach, a dendrimer buildingblock named dendron, and illustrated above, is used as “X” moiety,wherein the rest of NHE-inhibiting molecule is attached to one, severalor optionally all termini located at the periphery of the dendron. Thenumber of generations herein is typically between about 0 and about 6,and between about 0 and about 3. (Generation is defined in, for example,J. M. J. Fréchet, D. A. Tomalia, Dendrimers and Other DendriticPolymers, John Wiley & Sons, Ltd. NY, NY.) Dendrimer and/or dendronstructures are well known in the art and include, for example, thoseshown in or illustrated by: (i) J. M. J. Fréchet, D. A. Tomalia,Dendrimers and Other Dendritic Polymers, John Wiley & Sons, Ltd. NY, NY;(ii) George R Newkome, Charles N. Moorefield and Fritz Vogtle,Dendrimers and Dendrons: Concepts, Syntheses, Applications, VCHVerlagsgesellschaft Mbh; and, (iii) Boas, U., Christensen, J. B.,Heegaard, P.M.H., Dendrimers in Medicine and Biotechnology: NewMolecular Tools, Springer, 2006.

In yet another approach, the “X” moiety may be a polymer moiety or anoligomer moiety. The polymer or oligomer may, in each case, beindependently considered and comprise repeat units consisting of arepeat moiety selected from alkyl (e.g., —CH₂—), substituted alkyl(e.g., —CHR—, wherein, for example, R is hydroxy), alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, phenyl, aryl, heterocyclic,amine, ether, sulfide, disulfide, hydrazine, and any of the foregoingsubstituted with oxygen, sulfur, sulfonyl, phosphonyl, hydroxyl,alkoxyl, amine, thiol, ether, carbonyl, carboxyl, ester, amide, alkyl,alkenyl, alkynyl, aryl, heterocyclic, as well as moieties comprisingcombinations thereof. In still another approach, the “X” moietycomprises repeat units resulting from the polymerization of ethylenicmonomers (e.g., such as those ethylenic monomers listed elsewhere hereinbelow).

Preferred polymers for polymeric moieties useful in constructingsubstantially impermeable or substantially systemically non-bioavailableNHE-inhibiting compounds that are multivalent, for use in the treatmentvarious treatment methods disclosed herein, can be prepared by anysuitable technique, such as by free radical polymerization, condensationpolymerization, addition polymerization, ring-opening polymerization,and/or can be derived from naturally occurring polymers, such assaccharide polymers. Further, in some embodiments, any of these polymermoieties may be functionalized.

Examples of polysaccharides useful in preparation of such compoundsinclude but are not limited to materials from vegetable or animalorigin, including cellulose materials, hemicellulose, alkyl cellulose,hydroxyalkyl cellulose, carboxymethylcellulose, sulfoethylcellulose,starch, xylan, amylopectine, chondroitin, hyarulonate, heparin, guar,xanthan, mannan, galactomannan, chitin, and/or chitosan. More preferred,in at least some instances, are polymer moieties that do not degrade, orthat do not degrade significantly, under the physiological conditions ofthe GI tract (such as, for example, carboxymethylcellulose, chitosan,and sulfoethylcellulose).

When free radical polymerization is used, the polymer moiety can beprepared from various classes of monomers including, for example,acrylic, methacrylic, styrenic, vinylic, and dienic, whose typicalexamples are given thereafter: styrene, substituted styrene, alkylacrylate, substituted alkyl acrylate, alkyl methacrylate, substitutedalkyl methacrylate, acrylonitrile, methacrylonitrile, acrylamide,methacrylamide, N-alkylacrylamide, N-alkylmethacrylamide,N,N-dialkylacrylamide, N,N-dialkylmethacrylamide, isoprene, butadiene,ethylene, vinyl acetate, and combinations thereof. Functionalizedversions of these monomers may also be used and any of these monomersmay be used with other monomers as comonomers. For example, specificmonomers or comonomers that may be used in this disclosure includemethyl methacrylate, ethyl methacrylate, propyl methacrylate (allisomers), butyl methacrylate (all isomers), 2-ethylhexyl methacrylate,isobornyl methacrylate, methacrylic acid, benzyl methacrylate, phenylmethacrylate, methacrylonitrile, α-methylstyrene, methyl acrylate, ethylacrylate, propyl acrylate (all isomers), butyl acrylate (all isomers),2-ethylhexyl acrylate, isobornyl acrylate, acrylic acid, benzylacrylate, phenyl acrylate, acrylonitrile, styrene, glycidylmethacrylate, 2-hydroxyethyl methacrylate, hydroxypropyl methacrylate(all isomers), hydroxybutyl methacrylate (all isomers),N,N-dimethylaminoethyl methacrylate, N,N-diethylaminoethyl methacrylate,triethyleneglycol methacrylate, itaconic anhydride, itaconic acid,glycidyl acrylate, 2-hydroxyethyl acrylate, hydroxypropyl acrylate (allisomers), hydroxybutyl acrylate (all isomers), N,N-dimethylaminoethylacrylate, N,N-diethylaminoethyl acrylate, triethyleneglycol acrylate,methacrylamide, N-methylacrylamide, N,N-dimethylacrylamide,N-tert-butylmethacrylamide, N—N-butylmethacrylamide,N-methylolmethacrylamide, N-ethylolmethacrylamide,N-tert-butylacrylamide, N—N-butylacrylamide, N-methylolacrylamide,N-ethylolacrylamide, 4-acryloylmorpholine, vinyl benzoic acid (allisomers), diethylaminostyrene (all isomers), α-methylvinyl benzoic acid(all isomers), diethylamino α-methylstyrene (all isomers),p-vinylbenzenesulfonic acid, p-vinylbenzenesulfonic sodium salt, alkoxyand alkyl silane functional monomers, maleic anhydride,N-phenylmaleimide, N-butylmaleimide, butadiene, isoprene, chloroprene,ethylene, vinyl acetate, vinylformamide, allylamine, vinylpyridines (allisomers), fluorinated acrylate, methacrylates, and combinations thereof.Main chain heteroatom polymer moieties can also be used, includingpolyethyleneimine and polyethers such as polyethylene oxide andpolypropylene oxide, as well as copolymers thereof.

In one particular embodiment, the polymer to which the NHE-inhibitingmolecule is attached, or otherwise a part of, is a polyol (e.g., apolymer having a repeat unit of, for example, a hydroxy]-substitutedalkyl, such as —CH(OH)—). Polyols, such as mono- and disaccharides, withor without reducing or reducible end groups thereon, may be goodcandidates, for example, for installing additional functionality thatcould render the compound substantially impermeable.

In one particular embodiment, the NHE-inhibiting molecule is attached atone or both ends of the polymer chain. More specifically, in yet anotheralternative approach to the polyvalent embodiment of the presentdisclosure, a macromolecule (e.g., a polymer or oligomer) having thegeneric following exemplary structures

which may be exemplified, designed, and/or constructed as described forthe moieties:

It is understood that any embodiment of the compounds of the presentinvention, as set forth above, and any specific substituent set forthherein in such compounds, as set forth above, may be independentlycombined with other embodiments and/or substituents of such compounds toform embodiments of the inventions not specifically set forth above. Inaddition, in the event that a list of substituents is listed for anyparticular substituent in a particular embodiment and/or claim, it isunderstood that each individual substituent may be deleted from theparticular embodiment and/or claim and that the remaining list ofsubstituents will be considered to be within the scope of the invention.Furthermore, it is understood that in the present description,combinations of substituents and/or variables of the depicted formulaeare permissible only if such contributions result in stable compounds.

B. Permeability

In this regard it is to be noted that, in various embodiments, theability of a compound to be substantially systemically non-bioavailableis based on the compound charge, size, and/or other physicochemicalparameters (e.g., polar surface area, number of hydrogen bond donorsand/or acceptors therein, number of freely rotatable bonds, etc.). Morespecifically, it is to be noted that the absorption character of acompound can be selected by applying principles of pharmacodynamics, forexample, by applying Lipinski's rule, also known as “the rule of five.”Although not a rule, but rather a set of guidelines, Lipinski shows thatsmall molecule drugs with (i) a molecular weight, (ii) a number ofhydrogen bond donors, (iii) a number of hydrogen bond acceptors, and/or(iv) a water/octanol partition coefficient (Moriguchi Log P), greaterthan a certain threshold value, generally do not show significantsystemic concentration (i.e., are generally not absorbed to anysignificant degree). (See, e.g., Lipinski et al., Advanced Drug DeliveryReviews, 46, 2001 3-26, incorporated herein by reference.) Accordingly,substantially systemically non-bioavailable compounds (e.g.,substantially systemically non-bioavailable NHE-inhibiting compounds)can be designed to have molecular structures exceeding one or more ofLipinski's threshold values. (See also Lipinski et al., Experimental andComputational Approaches to Estimate Solubility and Permeability in DrugDiscovery and Development Settings, Adv. Drug Delivery Reviews, 46:3-26(2001); and Lipinski, Drug-like Properties and the Causes of PoorSolubility and Poor Permeability, J. Pharm. & Toxicol. Methods,44:235-249 (2000), incorporated herein by reference.) In someembodiments, for example, a substantially impermeable or substantiallysystemically non-bioavailable NHE-inhibiting compound of the presentdisclosure can be constructed to feature one or more of the followingcharacteristics: (i) a MW greater than about 500 Da, about 1000 Da,about 2500 Da, about 5000 Da, about 10,000 Da or more (in the non-saltform of the compound); (ii) a total number of NH and/or OH and/or otherpotential hydrogen bond donors greater than about 5, about 10, about 15or more; (iii) a total number of O atoms and/or N atoms and/or otherpotential hydrogen bond acceptors greater than about 5, about 10, about15 or more; and/or (iv) a Moriguchi partition coefficient greater thanabout 10⁵ (i.e., Log P greater than about 5, about 6, about 7, etc.), oralternatively less than about 10 (i.e., a Log P of less than 1, or even0).

In addition to the parameters noted above, the molecular polar surfacearea (i.e., “PSA”), which may be characterized as the surface belongingto polar atoms, is a descriptor that has also been shown to correlatewell with passive transport through membranes and, therefore, allowsprediction of transport properties of drugs. It has been successfullyapplied for the prediction of intestinal absorption and Caco2 cellmonolayer penetration. (For Caco2 cell monolayer penetration testdetails, see for example the description of the Caco2 Model provided inExample 31 of U.S. Pat. No. 6,737,423, the entire contents of which areincorporated herein by reference for all relevant and consistentpurposes, and the text of Example 31 in particular, which may be appliedfor example to the evaluation or testing of the compounds of the presentdisclosure.) PSA is expressed in {acute over (Å)}² (squared angstroms)and is computed from a three-dimensional molecular representation. Afast calculation method is now available (see, e.g., Ertl et al.,Journal of Medicinal Chemisiry, 2000, 43, 3714-3717, the entire contentsof which are incorporated herein by reference for all relevant andconsistent purposes) using a desktop computer and commercially availablechemical graphic tools packages, such as ChemDraw. The term “topologicalPSA” (tPSA) has been coined for this fast-calculation method. tPSA iswell correlated with human absorption data with common drugs (see, e.g.,Table 1, below):

TABLE 1 name % FA^(a) TPSA^(b) metoprolol 102 50.7 nordiazepam 99 41.5diazepam 97 32.7 oxprenolol 97 50.7 phenazone 97 26.9 oxazepam 97 61.7alprenolol 96 41.9 practolol 95 70.6 pindolol 92 57.3 ciprofloxacin 6974.6 metolazone 64 92.5 tranexamic acid 55 63.3 atenolol 54 84.6sulpiride 36 101.7 mannitol 26 121.4 foscarnet 17 94.8 sulfasalazine 12141.3 olsalazine 2.3 139.8 lactulose 0.6 197.4 raffinose 0.3 268.7(from Ertl et al., J. Med. Chem., 2000, 43:3714-3717). Accordingly, insome preferred embodiments, the compounds of the present disclosure maybe constructed to exhibit a tPSA value greater than about 100 Å², about120 Å², about 130 Å², or about 140 Å², and in some instances about 150Å², about 200 Å², about 250 Å², about 270 Å², about 300 Å², about 400Å², or even about 500 Å², such that the compounds are substantiallyimpermeable or substantially systemically non-bioavailable (as definedelsewhere herein).

Because there are exceptions to Lipinski's “rule,” or the tPSA model,the permeability properties of the compounds of the present disclosuremay be screened experimentally. The permeability coefficient can bedetermined by methods known to those of skill in the art, including forexample by Caco-2 cell permeability assay and/or using an artificialmembrane as a model of a gastrointestinal epithelial cell. (Aspreviously noted above, see for example U.S. Pat. No. 6,737,423, Example31 for a description of the Caco-2 Model, which is incorporated hereinby reference). A synthetic membrane impregnated with, for example,lecithin and/or dodecane to mimic the net permeability characteristicsof a gastrointestinal mucosa, may be utilized as a model of agastrointestinal mucosa. The membrane can be used to separate acompartment containing the compound of the present disclosure from acompartment where the rate of permeation will be monitored. Also,parallel artificial membrane permeability assays (PAMPA) can beperformed. Such in vitro measurements can reasonably indicate actualpermeability in vivo. (See, for example, Wohnsland et al., J. Med.Chem., 2001, 44:923-930; Schmidt et al., Millipore Corp. ApplicationNote, 2002, no AN1725EN00, and no AN1728EN00, incorporated herein byreference.)

Accordingly, in some embodiments, the compounds utilized in the methodsof the present disclosure may have a permeability coefficient, Papp, ofless than about 100×10⁻⁶ cm/s, or less than about 10×10⁻⁶ cm/s, or lessthan about 1×10⁻⁶ cm/s, or less than about 0.1×10⁻⁶ cm/s, when measuredusing means known in the art (such as for example the permeabilityexperiment described in Wohnsland et al., J. Med. Chem., 2001, 44,923-930, the contents of which is incorporated herein by reference).

As previously noted, in accordance with the present disclosure, aNHE-inhibiting compound is modified as described above to hinder the netabsorption through a layer of gut epithelial cells, rendering theresulting compound substantially systemically non-bioavailable. Invarious embodiments, the compounds of the present disclosure aresubstantially impermeable or substantially systemicallynon-bioavailable. More specifically, the NHE-inhibiting can be a dimer,multimer or polymer moiety, such that the resulting compound issubstantially impermeable or substantially systemicallynon-bioavailable. The dimer, multimer or polymer may be of a molecularweight greater than about 500 Daltons (Da), about 1000 Da, about 2500Da, about 5000 Da, about 10,000 Da or more, and in particular may have amolecular weight in the range of about 1000 Daltons (Da) to about500,000 Da, or in the range of about 5000 to about 200,000 Da, and mayhave a molecular weight that is sufficiently high to essentiallypreclude any net absorption through a layer of gut epithelial cells ofthe compound.

C. Persistent Inhibitory, Effect

In other embodiments, the substantially impermeable or substantiallysystemically non-bioavailable NHE-inhibiting compounds utilized in thetreatment methods of the present disclosure may additionally exhibit apersistent inhibitor effect. This effect manifests itself when theinhibitory action of a compound at a certain concentration inequilibrium with the epithelial cell (e.g., at or above its inhibitoryconcentration, IC) does not revert to baseline (i.e., sodium transportwithout inhibitor) after the compound is depleted by simple washing ofthe luminal content.

This effect can be interpreted as a result of the tight binding of theNHE-inhibiting compounds to the NHE protein at the intestinal apicalside of the gut epithelial cell. The binding can be considered asquasi-irreversible to the extent that, after the compound has beencontacted with the gut epithelial cell and subsequently washed off saidgut epithelial cell, the flux of sodium transport is still significantlylower than in the control without the compound. This persistentinhibitory effect has the clear advantage of maintaining drug activitywithin the GI tract even though the residence time of the active in theupper GI tract is short, and when no entero-biliary recycling process iseffective to replenish the compound concentration near its site ofaction.

Such a persistent inhibitory effect has an obvious advantage in terms ofpatient compliance, but also in limiting drug exposure within the GItract.

The persistence effect can be determined using in vitro methods; in oneinstance, cell lines expressing NHE transporters are split in differentvials and treated with a NHE-inhibiting compound and sodium solution tomeasure the rate of sodium uptake. The cells in one set of vials arewashed for different periods of time to remove the inhibitor, and sodiumuptake measurement is repeated after the washing. Compounds thatmaintain their inhibitory effect after multiple/lengthy washing steps(compared to the inhibitory effect measured in the vials where washingdoes not occur) are persistent inhibitors. Persistence effect can alsobe characterized ex vivo by using the everted sac technique, wherebytransport of Na is monitored using an excised segment of GI perfusedwith a solution containing the inhibitor and shortly after flushing thebathing solution with a buffer solution free from inhibitor. Apersistence effect can also be characterized in vivo by observing thetime needed for sodium balance to return to normal when the inhibitortreatment is discontinued. The limit of the method resides in the factthat apical cells (and therefore apical NHE transporters) are sloughedoff after a period of 3 to 4 days, the typical turnover time of gutepithelial cells. A persistence effect can be achieved by increasing theresidence time of the active compound at the apical surface of the gutepithelial cells; this can be obtained by designing NHE antiportinhibitors with several NHE-inhibiting molecule or oligomer (wherein“several” as used herein typically means at least about 2, about 4,about 6 or more). Examples of such structures in the context of analogsof the antibiotic vancomycin are given in Griffin, et al., J. Am. Chem.Soc., 2003, 125, 6517-6531. Alternatively the compound comprises groupsthat contribute to increase the affinity towards the gut epithelial cellso as to increase the time of contact with the gut epithelial cellsurface. Such groups are referred to as being “mucoadhesive.” Morespecifically, the “X” and Linker moieties can be substituted by suchmucoadhesive groups, such as polyacrylates, partially deacetylatedchitosan or polyalkylene glycol. (See also Patil, S. B. et al., Curr.Drug. Deliv., 2008, Oct. 5(4), pp. 312-8.) Compounds of the inventionincorporating a cyano group at the 4-position of the indane ring systemof formula I unexpectedly exhibited superior persistent inhibition ofNHE3 in the cell-based assay described in example 181 herein incomparison to compounds incorporating other groups at said positions 4and 6. For example, compounds incorporating 4-cyano and 6-chloro groupsdemonstrated superior persistent inhibition compared to the analagouscompound having a 4,6-dichloro substituted indane ring system. Seefollowing table. The following pairs of compounds differ only in the4-position substituent (either chloro (X-Cl) or cyano (X-CN)):

-   (A-Cl)    3-(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2    S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino}butyl)urea;    and-   (A-CN)    3-(2-{2-[(3R)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3R)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)urea.-   (B-Cl)    N-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl]-2-({[4-({[({2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}carbamoyl)methyl]carbamoyl}amino)butyl]carbamoyl}amino)acetamide;    and-   (B-CN) N-{2-[(3    S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}-2-({[4-({[({2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}carbamoyl)methyl]carbamoyl}amino)butyl]carbamoyl}amino)acetamide.-   (C-Cl)    3-(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)urea;    and-   (C-CN)    3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy)ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea.-   (C-Cl)    3-(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)urea;    and-   (C-CN)    3-(2-[2-[(3S)-3-[4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-[2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)urea.-   (D-Cl)    3-(2-{2-[2-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea;    and

(D-CN)3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea.

-   (E-Cl)    3-(2-{2-[2-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-[(4-({(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea;    and-   (E-CN)    3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea.-   (F-Cl)    3-(2-{2-[2-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-methylbenzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-methylbenzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea;    and-   (F-CN)    3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-methylbenzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2    S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-methylbenzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea.-   (G-Cl)    3-(2-{2-[2-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea;    and-   (G-CN)    3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea.

pIC50 Standard Percent Compound (persistent) Deviation n Inhibition A-Cl8.6 0.2 3 101 A-CN 9.2 0.1 2 101 B-Cl 9.2 0 2 102 B-CN 9.9 0.1 6 110C-Cl 8.4 0.1 2 90 C-CN 9.3 0.3 3 106 D-Cl 8.4 0.1 2 — D-CN 9.3 0.1 2 74E-Cl 8.3 0.3 5 99 E-CN 8.9 0.8 4 36 F-Cl 7.7 0.2 5 104 F-CN 8.6 0.1 2 88G-Cl 8.2 0.1 2 82 G-CN 9.0 0.2 2 —

Accordingly, in an embodiment of the invention there is provided acompound having a structure according to any one of formula (I′) and(Ia′) through (Ii′).

D. GI Enzyme Resistance

Because the compounds utilized in the treatment methods of the presentdisclosure are substantially systemically non-bioavailable, and/orexhibit a persistent inhibitory effect, it is also desirable that,during their prolonged residence time in the gut, these compoundssustain the hydrolytic conditions prevailing in the upper GI tract. Insuch embodiments, compounds of the present disclosure are resistant toenzymatic metabolism. For example, administered compounds are resistantto the activity of P450 enzymes, glucurosyl transferases,sulfotransferases, glutathione S-transferases, and the like, in theintestinal mucosa, as well as gastric (e.g., gastric lipase, andpepsine), pancreatic (e.g., trypsin, triglyceride pancreatic lipase,phospholipase A2, endonucleases, nucleotidases, and alpha-amylase), andbrush-border enzymes (e.g., alkaline phosphatase, glycosidases, andproteases) generally known in the art.

The compounds that are utilized in methods of the present disclosure arealso resistant to metabolism by the bacterial flora of the gut; that is,the compounds are not substrates for enzymes produced by bacterialflora. In addition, the compounds administered in accordance with themethods of the present disclosure may be substantially inactive towardsthe gastrointestinal flora, and do not disrupt bacterial growth orsurvival. As a result, in various embodiments herein, the minimalinhibitory concentration (or “MIC”) against GI flora is desirablygreater than about 15 μg/ml, about 30 μg/ml, about 60 μg/ml, about 120μg/ml, or even about 240 μg/ml, the MIC in various embodiments being forexample between about 16 and about 32 μg/ml, or between about 64 andabout 128 μg/ml, or greater than about 256 μg/ml.

To one skilled in the art of medicinal chemistry, metabolic stabilitycan be achieved in a number of ways. Functionality susceptible toP450-mediated oxidation can be protected by, for example, blocking thepoint of metabolism with a halogen or other functional group.Alternatively, electron withdrawing groups can be added to a conjugatedsystem to generally provide protection to oxidation by reducing theelectrophilicity of the compound. Proteolytic stability can be achievedby avoiding secondary amide bonds, or by incorporating changes instereochemistry or other modifications that prevent the drug fromotherwise being recognized as a substrate by the metabolizing enzyme.

E. Sodium and/or Fluid Output

It is also to be noted that, in various embodiments of the presentdisclosure, one or more of the NHE-inhibiting compounds detailed herein,when administered either alone or in combination with one or moreadditional pharmaceutically active compounds or agents (including, forexample, a fluid-absorbing polymer) to a patient in need thereof, mayact to increase the patient's daily fecal output of sodium by at leastabout 20, about 30 mmol, about 40 mmol, about 50 mmol, about 60 mmol,about 70 mmol, about 80 mmol, about 90 mmol, about 100 mmol, about 125mmol, about 150 mmol or more, the increase being for example within therange of from about 20 to about 150 mmol/day, or from about 25 to about100 mmol/day, or from about 30 to about 60 mmol/day

Additionally, or alternatively, it is also to be noted that, in variousembodiments of the present disclosure, one or more of the NHE-inhibitingcompounds detailed herein, when administered either alone or incombination with one or more additional pharmaceutically activecompounds or agents (including, for example, a fluid-absorbing polymer)to a patent in need thereof, may act to increase the patient's dailyfluid output by at least about 100 ml, about 200 ml, about 300 ml, about400 ml, about 500 ml, about 600 ml, about 700 ml, about 800 ml, about900 ml, about 1000 ml or more, the increase being for example within therange of from about 100 to about 1000 ml/day, or from about 150 to about750 ml/day, or from about 200 to about 500 nl/day (assuming isotonicfluid).

F. C_(max) and IC₅₀

It is also to be noted that, in various embodiments of the presentdisclosure, one or more of the NHE-inhibiting compounds detailed herein,when administered either alone or in combination with one or moreadditional pharmaceutically active compounds or agents (including, forexample, a fluid-absorbing polymer) to a patient in need thereof at adose resulting in at least a 10% increase in fecal water content, has aC_(max) that is less than the IC₅₀ for NHE-3, more specifically, lessthan about 10× (10 times) the IC₅₀, and, more specifically still, lessthan about 100× (100 times) the IC₅₀.

Additionally, or alternatively, it is also to be noted that, in variousembodiments of the present disclosure, one or more of the NHE-inhibitingcompounds detailed herein, when administered either alone or incombination with one or more additional pharmaceutically activecompounds or agents (including, for example, a fluid-absorbing polymer)to a patient in need thereof, may have a C_(max) of less than about 10ng/ml, about 7.5 ng/ml, about 5 ng/ml, about 2.5 ng/ml, about 1 ng/ml,or about 0.5 ng/ml, the C_(max) being for example within the range ofabout 1 ng/ml to about 10 ng/ml, or about 2.5 ng/ml to about 7.5 ng/ml.

Additionally, or alternatively, it is also to be noted that, in variousembodiments of the present disclosure, one or more of the NHE-inhibitingcompounds detailed herein, when administered either alone or incombination with one or more additional pharmaceutically activecompounds or agents (including, for example, a fluid-absorbing polymer)to a patient in need thereof, may have a IC₅₀ of less than about 10 μM,about 7.5 μM, about 5 μM, about 2.5 μM, about 1 μM, or about 0.5 μM, theIC₅₀ being for example within the range of about 1 μM to about 10 μM, orabout 2.5 μM to about 7.5 μM.

Additionally, or alternatively, it is also to be noted that, in variousembodiments of the present disclosure, one or more of the NHE-inhibitingcompounds detailed herein, when administered to a patient in needthereof, may have a ratio of IC₅₀:C_(max), wherein IC₅₀ and C_(max) areexpressed in terms of the same units, of at least about 10, about 50,about 100, about 250, about 500, about 750, or about 1000.

Additionally, or alternatively, it is also to be noted that, in variousembodiments of the present disclosure, wherein one or more of theNHE-inhibiting compounds as detailed herein is orally administered to apatent in need thereof, within the therapeutic range or concentration,the maximum compound concentration detected in the serum, defined asC_(max), is lower than the NHE inhibitory concentration IC₅₀ of saidcompound. As previously noted, as used herein, IC₅₀ is defined as thequantitative measure indicating the concentration of the compoundrequired to inhibit 50% of the NHE-mediated Na/H antiport activity in acell based assay.

III. Pharmaceutical Compositions and Methods of Treatment

A Compositions and Methods

1. Fluid Retention and/or Salt Overload Disorders

Another aspect of the invention is directed to method for inhibitingNHE-mediated antiport of sodium and hydrogen ions. The method comprisesadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound or pharmaceutical composition of Formula I. In oneembodiment, the method comprises administering to a mammal in needthereof a pharmaceutically effective amount of a compound Ia, Ib, Ic,Id, Ie, If, Ig, Ih, or Ii or a combination thereof.

Another aspect of the invention is directed to method for treating adisorder associated with fluid retention or salt overload. The methodcomprises administering to a mammal in need thereof a pharmaceuticallyeffective amount of a compound or pharmaceutical composition of FormulaI. In one embodiment, the method of treating a disorder associated withfluid retention or salt overload comprises administering to a mammal inneed thereof a pharmaceutically effective amount of a compound Ia, Ib,Ic, Id, Ie, If, Ig, Ih, or Ii or a combination thereof.

In one embodiment, a method for treating a disorder selected from thegroup consisting of heart failure (such as congestive heart failure),chronic kidney disease, end-stage renal disease, liver disease, andperoxisome proliferator-activated receptor (PPAR) gamma agonist-inducedfluid retention is provided, the method comprising administering to amammal in need thereof a pharmaceutically effective amount of a compoundor pharmaceutical composition as set forth above. In another embodiment,the disorder is, but not limited to, a gastrointestinal motilitydisorder, irritable bowel syndrome, chronic constipation, chronicidiopathic constipation, chronic constipation occurring in cysticfibrosis patients, chronic constipation occurring in chronic kidneydisease patients, calcium-induced constipation in osteoporotic patients,opioid-induced constipation, a functional gastrointestinal tractdisorder, gastroesophageal reflux disease, functional heartburn,dyspepsia, functional dyspepsia, non-ulcer dyspepsia, gastroparesis,chronic intestinal pseudo-obstruction, Crohn's disease, ulcerativecolitis and related diseases referred to as inflammatory bowel syndrome,colonic pseudo-obstruction, gastric ulcers, infectious diarrhea, cancer(colorectal), “leaky gut syndrome”, cystic fibrosis gastrointestinaldisease, multi-organ failure, microscopic colitis, necrotizingenterocolitis, allergy—atopy, food allergy, infections (respiratory),acute inflammation (e.g., sepsis, systemic inflammatory responsesyndrome), chronic inflammation (arthritis), obesity-induced metabolicdiseases (e.g., nonalcoholic steatohepatitis, Type I diabetes, Type IIdiabetes, cardiovascular disease), kidney disease, diabetic kidneydisease, cirrhosis, nonalcoholic steatohepatitis, nonalcoholic fattyacid liver disease, Steatosis, primary sclerosing cholangitis, primarybiliary cholangitis, portal hypertension, autoimmune disease (e.g., TypeI diabetes, ankylosing spondylitis, lupus, alopecia areata, rheumatoidarthritis, polymyalgia rheumatica, fibromyalgia, chronic fatiguesyndrome, Sjogren's syndrome, vitiligo, thyroiditis, vasculitis,urticarial (hives), Raynaud's syndrome), Schizophrenia, autism spectrumdisorders, hepatic encephlopathy, chronic alcoholism, and the like.

In another embodiment, a method for treating hypertension is provided,the method comprising administering to a mammal in need thereof apharmaceutically effective amount of a compound or pharmaceuticalcomposition as set forth above.

In further embodiments, the method comprises administering apharmaceutically effective amount of the compound to the mammal in orderto increase the mammal's daily fecal output of sodium and/or fluid. Infurther embodiments, the method comprises administering apharmaceutically effective amount of the compound to the mammal in orderto increase the mammal's daily fecal output of sodium by at least about30 mmol, and/or fluid by at least about 200 ml. In further embodiments,the mammal's fecal output of sodium and/or fluid is increased withoutintroducing another type of cation in a stoichiometric or nearstoichiometric fashion via an ion exchange process. In furtherembodiments, the method further comprises administering to the mammal afluid-absorbing polymer to absorb fecal fluid resulting from the use ofthe compound that is substantially active in the gastrointestinal tractto inhibit NHE-mediated antiport of sodium ions and hydrogen ionstherein.

In further embodiments, the compound or composition is administered totreat hypertension. In further embodiments, the compound or compositionis administered to treat hypertension associated with dietary saltintake. In further embodiments, administration of the compound orcomposition allows the mammal to intake a more palatable diet. Infurther embodiments, the compound or composition is administered totreat fluid overload. In further embodiments, the fluid overload isassociated with congestive heart failure. In further embodiments, thefluid overload is associated with end stage renal disease. In furtherembodiments, the fluid overload is associated with peroxisomeproliferator-activated receptor (PPAR) gamma agonist therapy. In furtherembodiments, the compound or composition is administered to treat sodiumoverload. In further embodiments, the compound or composition isadministered to reduce interdialytic weight gain in ESRD patients. Infurther embodiments, the compound or composition is administered totreat edema. In further embodiments, the edema is caused bychemotherapy, pre-menstrual fluid overload or preeclampsia.

In further embodiments, the compound or composition is administered totreat gastric ulcers. In further embodiments, the compound orcomposition is administered to treat infectious diarrhea. In furtherembodiments, the compound or composition is administered to treat cancer(colorectal). In further embodiments, the compound or composition isadministered to treat “leaky gut syndrome”. In further embodiments, thecompound or composition is administered to treat cystic fibrosisgastrointestinal disease. In further embodiments, the compound orcomposition is administered to treat multi-organ failure. In furtherembodiments, the compound or composition is administered to treatmicroscopic colitis. In further embodiments, the compound or compositionis administered to treat necrotizing enterocolitis. In furtherembodiments, the compound or composition is administered to treat atopy.In further embodiments, the compound or composition is administered totreat food allergy. In further embodiments, the compound or compositionis administered to treat respiratory infections. In further embodiments,the compound or composition is administered to treat acute inflammation(e.g., sepsis, systemic inflammatory response syndrome). In furtherembodiments, the compound or composition is administered to treatchronic inflammation (e.g., arthritis). In further embodiments, thecompound or composition is administered to treat obesity-inducedmetabolic diseases (e.g., nonalcoholic steatohepatitis, Type I diabetes,Type II diabetes, cardiovascular disease). In further embodiments, thecompound or composition is administered to treat kidney disease. Infurther embodiments, the compound or composition is administered totreat diabetic kidney disease. In further embodiments, the compound orcomposition is administered to treat cirrhosis. In further embodiments,the compound or composition is administered to treat steatohepatitis. Infurther embodiments, the compound or composition is administered totreat nonalcoholic fatty acid liver disease. In further embodiments, thecompound or composition is administered to treat steatosis. In furtherembodiments, the compound or composition is administered to treatprimary sclerosing cholangitis. In further embodiments, the compound orcomposition is administered to treat primary biliary cholangitis. Infurther embodiments, the compound or composition is administered totreat portal hypertension. In further embodiments, the compound orcomposition is administered to treat autoimmune disease (e.g., Type Idiabetes, ankylosing spondylitis, lupus, alopecia areata, rheumatoidarthritis, polymyalgia rheumatica, fibromyalgia, chronic fatiguesyndrome, Sjogren's syndrome, vitiligo, thyroiditis, vasculitis,urticarial (hives), or Raynaud's syndrome). In further embodiments, thecompound or composition is administered to treat Schizophrenia. Infurther embodiments, the compound or composition is administered totreat autism spectrum disorders. In further embodiments, the compound orcomposition is administered to treat hepatic encephlopathy. In furtherembodiments, the compound or composition is administered to treatchronic alcoholism.

In further embodiments, the compound or composition is administeredorally, by rectal suppository, or enema.

In further embodiments, the method comprises administering apharmaceutically effective amount of the compound or composition incombination with one or more additional pharmaceutically activecompounds or agents. In further embodiments, the one or more additionalpharmaceutically active compounds or agents is selected from the groupconsisting of a diuretic, cardiac glycoside, ACE inhibitor,angiotensin-2 receptor antagonist, aldosterone antagonist, aldosteronesynthase inhibitor, renin inhibitor, calcium channel blocker, betablocker, alpha blocker, central alpha agonist, vasodilator, bloodthinner, anti-platelet agent, lipid-lowering agent, and peroxisomeproliferator-activated receptor (PPAR) gamma agonist agent. In furtherembodiments, the diuretic is selected from the group consisting of ahigh ceiling loop diuretic, a benzothiadiazide diuretic, a potassiumsparing diuretic, and an osmotic diuretic. In further embodiments, thepharmaceutically effective amount of the compound or composition, andthe one or more additional pharmaceutically active compounds or agents,are administered as part of a single pharmaceutical preparation. Infurther embodiments, the pharmaceutically effective amount of thecompound or composition, and the one or more additional pharmaceuticallyactive compounds or agents, are administered as individualpharmaceutical preparations. In further embodiments, the individualpharmaceutical preparation is administered sequentially. In furtherembodiments, the individual pharmaceutical preparation is administeredsimultaneously.

In another embodiment, a method for treating a gastrointestinal tractdisorder is provided, the method comprising administering to a mammal inneed thereof a pharmaceutically effective amount of a compound orpharmaceutical composition as set forth above.

In further embodiments, the gastrointestinal tract disorder is agastrointestinal motility disorder. In further embodiments, thegastrointestinal tract disorder is irritable bowel syndrome. In furtherembodiments, the gastrointestinal tract disorder is chronicconstipation. In further embodiments, the gastrointestinal tractdisorder is chronic idiopathic constipation. In further embodiments, thegastrointestinal tract disorder is chronic constipation occurring incystic fibrosis patients. In further embodiments, the gastrointestinaltract disorder is opioid-induced constipation. In further embodiments,the gastrointestinal tract disorder is a functional gastrointestinaltract disorder. In further embodiments, the gastrointestinal tractdisorder is selected from the group consisting of chronic intestinalpseudo-obstruction and colonic pseudo-obstruction. In furtherembodiments, the gastrointestinal tract disorder is Crohn's disease. Infurther embodiments, the gastrointestinal tract disorder is ulcerativecolitis. In further embodiments, the gastrointestinal tract disorder isa disease referred to as inflammatory bowel disease. In furtherembodiments, the gastrointestinal tract disorder is associated withchronic kidney disease (stage 4 or 5). In further embodiments, thegastrointestinal tract disorder is constipation induced by calciumsupplement. In further embodiments, the gastrointestinal tract disorderis constipation, and the constipation to be treated is associated withthe use of a therapeutic agent. In further embodiments, thegastrointestinal tract disorder is constipation, and the constipation tobe treated is associated with a neuropathic disorder. In furtherembodiments, the gastrointestinal tract disorder is constipation, andthe constipation to be treated is post-surgical constipation(postoperative ileus). In further embodiments, the gastrointestinaltract disorder is constipation, and the constipation to be treated isidiopathic (functional constipation or slow transit constipation). Infurther embodiments, the gastrointestinal tract disorder isconstipation, and the constipation to be treated is associated withneuropathic, metabolic or an endocrine disorder (e.g., diabetesmellitus, renal failure, hypothyroidism, hyperthyroidism, hypocalcaemia,Multiple Sclerosis, Parkinson's disease, spinal cord lesions,neurofibromatosis, autonomic neuropathy, Chagas disease, Hirschsprung'sdisease or cystic fibrosis, and the like). In further embodiments, thegastrointestinal tract disorder is constipation, and the constipation tobe treated is due the use of drugs selected from analgesics (e.g.,opioids), antihypertensives, anticonvulsants, amidepressants,antispasmodics and antipsychotics.

In other embodiments, the gastrointestinal tract disorder is associatedwith gastric ulcers, infectious diarrhea, cancer (colorectal), “leakygut syndrome”, cystic fibrosis gastrointestinal disease, multi-organfailure, microscopic colitis, necrotizing enterocolitis, allergy—atopy,food allergy, infections (respiratory), acute inflammation (e.g.,sepsis, systemic inflammatory response syndrome), chronic inflammation(e.g., arthritis), obesity-induced metabolic diseases (e.g.,nonalcoholic steatohepatitis, Type I diabetes, Type II diabetes,cardiovascular disease), kidney disease, diabetic kidney disease,cirrhosis, nonalcoholic steatohepatitis, nonalcoholic fatty acid liverdisease, Steatosis, primary sclerosing cholangitis, primary biliarycholangitis, portal hypertension, autoimmune (e.g., Type I diabetes,ankylosing spondylitis, lupus, alopecia areata, rheumatoid arthritis,polymyalgia rheumatica, fibromyalgia, chronic fatigue syndrome,Sjogren's syndrome, vitiligo, thyroiditis, vasculitis, urticarial(hives), or Raynaud's syndrome), Schizophrenia, autism spectrumdisorders, hepatic encephlopathy, small intestitinal bacterialovergrowth, or chronic alcoholism.

In another embodiment, a method for treating irritable bowel syndrome isprovided, the method comprising administering to a mammal in needthereof a pharmaceutically effective amount of a compound orpharmaceutical composition as set forth above.

In further embodiments of the above embodiments, the compound orcomposition is administered to treat or reduce pain associated with agastrointestinal tract disorder. In further embodiments, the compound orcomposition is administered to treat or reduce visceral hypersensitivityassociated with a gastrointestinal tract disorder. In furtherembodiments, the compound or composition is administered to treat orreduce inflammation of the gastrointestinal tract. In furtherembodiments, the compound or composition is administered to reducegastrointestinal transit time.

Compounds of the invention inhibit Transient Receptor Potential Cationchannel subfamily C, member 6 (TRPC6). Accordingly, compounds of theinvention are useful for treating diseases, disorders and conditionsmediated with abherent TRPC6 activity, for example, cardiac hypertrophykidney diseases, in particular, glomerular diseases.

In further embodiments, the compound or composition is administeredeither orally or by rectal suppository.

In further embodiments, the method comprises administering apharmaceutically effective amount of the compound or composition, incombination with one or more additional pharmaceutically activecompounds or agents. In further embodiments, the one or more additionalpharmaceutically active agents or compounds are an analgesic peptide oragent. In further embodiments, the one or more additionalpharmaceutically active agents or compounds are selected from the groupconsisting of a laxative agent selected from a bulk-producing agent(e.g. psyllium husk (Metamucil)), methylcellulose (Citrucel),polycarbophil, dietary fiber, apples, stool softeners/surfactant (e.g.,docusate, Colace, Diocto), a hydrating or osmotic agent (e.g., dibasicsodium phosphate, magnesium citrate, magnesium hydroxide (Milk ofmagnesia), magnesium sulfate (which is Epsom salt), monobasic sodiumphosphate, sodium biphosphate), and a hyperosmotic agent (e.g., glycerinsuppositories, sorbitol, lactulose, and polyethylene glycol (PEG)). Infurther embodiments, the pharmaceutically effective amount of thecompound or composition, and the one or more additional pharmaceuticallyactive compounds or agents, are administered as part of a singlepharmaceutical preparation. In further embodiments, the pharmaceuticallyeffective amount of the compound or composition, and the one or moreadditional pharmaceutically active compounds or agents, are administeredas individual pharmaceutical preparations. In further embodiments, theindividual pharmaceutical preparation is administered sequentially. Infurther embodiments, the individual pharmaceutical preparation isadministered simultaneously.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula I and a pharmaceuticallyacceptable carrier. In one embodiment, the pharmaceutical compositioncomprise a compound of Formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, or Ii anda pharmaceutically acceptable carrier. In another embodiment, thepharmaceutical composition described herein may be used to inhibitNHE-mediated antiport of sodium and hydrogen ions. In anotherembodiment, the pharmaceutical composition described herein may be usedto treat disorders associated with fluid retention or salt overload

A pharmaceutical composition or preparation that may be used inaccordance with the present disclosure for the treatment of variousdisorders associated with fluid retention and/or salt overload in thegastrointestinal tract (e.g., hypertension, heart failure (inparticular, congestive heart failure), chronic kidney disease, end-stagerenal disease, liver disease and/or peroxisome proliferator-activatedreceptor (PPAR) gamma agonist-induced fluid retention) comprises, ingeneral, the substantially impermeable or substantially systemicallynon-bioavailable NHE-inhibiting compound of the present disclosure, aswell as various other optional components as further detailed hereinbelow (e.g., pharmaceutically acceptable excipients, etc.). Thecompounds utilized in the treatment methods of the present disclosure,as well as the pharmaceutical compositions comprising them, mayaccordingly be administered alone, or as part of a treatment protocol orregiment that includes the administration or use of other beneficialcompounds (as further detailed elsewhere herein). In some particularembodiments, the NHE-inhibiting compound, including any pharmaceuticalcomposition comprising the compound, is administered with afluid-absorbing polymer (as more fully described below).

Subjects “in need of treatment” with a compound of the presentdisclosure, or subjects “in need of NHE inhibition” include subjectswith diseases and/or conditions that can be treated with substantiallyimpermeable or substantially systemically non-bioavailableNHE-inhibiting compounds, with or without a fluid-absorbing polymer, toachieve a beneficial therapeutic and/or prophylactic result. Abeneficial outcome includes a decrease in the severity of symptoms ordelay in the onset of symptoms, increased longevity and/or more rapid ormore complete resolution of the disease or condition. For example, asubject in need of treatment may be suffering from hypertension; fromsalt-sensitive hypertension which may result from dietary salt intake;from a risk of a cardiovascular disorder (e.g., myocardial infarction,congestive heart failure and the like) resulting from hypertension; fromheart failure (e.g., congestive heart failure) resulting in fluid orsalt overload; from chronic kidney disease resulting in fluid or saltoverload, from end stage renal disease resulting in fluid or saltoverload; from liver disease resulting in fluid or salt overload; fromperoxisome proliferator-activated receptor (PPAR) gamma agonist-inducedfluid retention; or from edema resulting from congestive heart failureor end stage renal disease. In various embodiments, a subject in need oftreatment typically shows signs of hypervolemia resulting from salt andfluid retention that are common features of congestive heart failure,renal failure or liver alopeccia. Fluid retention and salt retentionmanifest themselves by the occurrence of shortness of breath, edema,ascites or interdialytic weight gain. Other examples of subjects thatwould benefit from the treatment are those suffering from congestiveheart failure and hypertensive patients and, particularly, those who areresistant to treatment with diuretics, i.e., patients for whom very fewtherapeutic options are available. A subject “in need of treatment” alsoincludes a subject with hypertension, salt-sensitive blood pressure andsubjects with systolic/diastolic blood pressure greater than about130-139/85-89 mm Hg.

Administration of NHE-inhibiting compounds, with or withoutadministration of fluid-absorbing polymers, may be beneficial forpatients put on “non-added salt” dietary regimen (i.e., 60-100 mmol ofNa per day), to liberalize their diet while keeping a neutral orslightly negative sodium balance (i.e., the overall uptake of salt wouldbe equal of less than the secreted salt). In that context, “liberalizetheir diet” means that patients treated may add salt to their meals tomake the meals more palatable, or/and diversify their diet withsalt-containing foods, thus maintaining a good nutritional status whileimproving their quality of life.

The treatment methods described herein may also help patients with edemaassociated with chemotherapy, pre-menstrual fluid overload andpreeclampsia (pregnancy-induced hypertension).

Accordingly, it is to be noted that the present disclosure is furtherdirected to methods of treatment involving the administration of thecompound of the present disclosure, or a pharmaceutical compositioncomprising such a compound. Such methods may include, for example, amethod for treating hypertension, the method comprising administering tothe patient a substantially impermeable or substantially systemicallynon-bioavailable NHE-inhibiting compound, or a pharmaceuticalcomposition comprising it. The method may be for reducing fluid overloadassociated with heart failure (in particular, congestive heart failure),the method comprising administering to the patient a substantiallyimpermeable or substantially systemically non-bioavailableNHE-inhibiting compound or pharmaceutical composition comprising it. Themethod may be for reducing fluid overload associated with end stagerenal disease, the method comprising administering to the patient asubstantially impermeable or substantially systemically non-bioavailableNHE-inhibiting compound or composition comprising it. The method may befor reducing fluid overload associated with peroxisomeproliferator-activated receptor (PPAR) gamma agonist therapy, the methodcomprising administering to the patient a substantially impermeable orsubstantially systemically non-bioavailable NHE-inhibiting compound orcomposition comprising it. Additionally, or alternatively, the methodmay be for decreasing the activity of an intestinal NHE transporter in apatient, the method comprising: administering to the patient asubstantially impermeable or substantially systemically non-bioavailableNHE-inhibiting compound, or a composition comprising it. In anotherembodiment, the disease to be treated, includes, but is not limited to,heart failure (such as congestive heart failure), chronic kidneydisease, end-stage renal disease, liver disease, and peroxisomeproliferator-activated receptor (PPAR) gamma agonist-induced fluidretention is provided, gastrointestinal motility disorder, irritablebowel syndrome, chronic constipation, chronic idiopathic constipation,chronic constipation occurring in cystic fibrosis patients, chronicconstipation occurring in chronic kidney disease patients,calcium-induced constipation in osteoporotic patients, opioid-inducedconstipation, a functional gastrointestinal tract disorder,gastroesophageal reflux disease, functional heartburn, dyspepsia,functional dyspepsia, non-ulcer dyspepsia, gastroparesis, chronicintestinal pseudo-obstruction, Crohn's disease, ulcerative colitis andrelated diseases referred to as inflammatory bowel syndrome, colonicpseudo-obstruction, gastric ulcers, infectious diarrhea, cancer(colorectal), “leaky gut syndrome”, cystic fibrosis gastrointestinaldisease, multi-organ failure, microscopic colitis, necrotizingenterocolitis, allergy—atopy, food allergy, infections (respiratory),acute inflammation (e.g., sepsis, systemic inflammatory responsesyndrome), chronic inflammation (arthritis), obesity-induced metabolicdiseases (e.g., nonalcoholic steatohepatitis, Type I diabetes, Type IIdiabetes, cardiovascular disease), kidney disease, diabetic kidneydisease, cirrhosis, nonalcoholic steatohepatitis, nonalcoholic fattyacid liver disease, Steatosis, primary sclerosing cholangitis, primarybiliary cholangitis, portal hypertension, autoimmune disease (e.g., TypeI diabetes, ankylosing spondylitis, lupus, alopecia areata, rheumatoidarthritis, polymyalgia rheumatica, fibromyalgia, chronic fatiguesyndrome, Sjogren's syndrome, vitiligo, thyroiditis, vasculitis,urticarial (hives), Raynaud's syndrome), Schizophrenia, autism spectrumdisorders, hepatic encephlopathy, small intestitinal bacterialovergrowth, and chronic alcoholism, and the like.

2. Gastrointestinal Tract Disorders

Another aspect of the invention is directed to method for treating adisorder associated with gastrointestinal tract. The method comprisesadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound or pharmaceutical composition of Formula I. In oneembodiment, the method of treating a disorder associated withgastrointestinal tract comprises administering to a mammal in needthereof a pharmaceutically effective amount of a compound Ia, Ib, Ic,Id, Ie, If, Ig, Ih, or Ii or a combination thereof.

A pharmaceutical composition or preparation that may be used inaccordance with the present disclosure for the treatment of variousgastrointestinal tract disorders, including the treatment or reductionof pain associated with gastrointestinal tract disorders, comprises, thesubstantially impermeable or substantially systemically non-bioavailableNHE-inhibiting compound of the present disclosure, as well as variousother optional components as further detailed herein below (e.g.,pharmaceutically acceptable excipients, etc.). The compounds utilized inthe treatment methods of the present disclosure, as well as thepharmaceutical compositions comprising them, may accordingly beadministered alone, or as part of a treatment protocol or regiment thatincludes the administration or use of other beneficial compounds (asfurther detailed elsewhere herein). In some particular embodiments, theNHE-inhibiting compound, including any pharmaceutical compositioncomprising the compound, is administered with a fluid-absorbing polymer(as more fully described below).

Subjects “in need of treatment” with a compound of the presentdisclosure, or subjects “in need of NHE inhibition” include subjectswith diseases and/or conditions that can be treated with substantiallyimpermeable or substantially systemically non-bioavailableNHE-inhibiting compounds, with or without a fluid-absorbing polymer, toachieve a beneficial therapeutic and/or prophylactic result. Abeneficial outcome includes a decrease in the severity of symptoms ordelay in the onset of symptoms, increased longevity and/or more rapid ormore complete resolution of the disease or condition. For example, asubject in need of treatment is suffering from a gastrointestinal tractdisorder; the patient is suffering from a disorder selected from thegroup consisting of: a gastrointestinal motility disorder, irritablebowel syndrome, chronic constipation, chronic idiopathic constipation,chronic constipation occurring in cystic fibrosis patients, chronicconstipation occurring in chronic kidney disease patients,calcium-induced constipation in osteoporotic patients, opioid-inducedconstipation, a functional gastrointestinal tract disorder,gastroesophageal reflux disease, functional heartburn, dyspepsia,functional dyspepsia, non-ulcer dyspepsia, gastroparesis, chronicintestinal pseudo-obstruction, Crohn's disease, ulcerative colitis andrelated diseases referred to as inflammatory bowel syndrome, colonicpseudo-obstruction, gastric ulcers, infectious diarrhea, cancer(colorectal), “leaky gut syndrome”, cystic fibrosis gastrointestinaldisease, multi-organ failure, microscopic colitis, necrotizingenterocolitis, atopy, food allergy, infections (respiratory), acuteinflammation (e.g., sepsis, systemic inflammatory response syndrome),chronic inflammation (e.g., arthritis), obesity-induced metabolicdiseases (e.g., nonalcoholic steatohepatitis, Type I diabetes, Type I1diabetes, cardiovascular disease), kidney disease, diabetic kidneydisease, cirrhosis, nonalcoholic steatohepatitis, nonalcoholic fattyacid liver disease, Steatosis, primary sclerosing cholangitis, primarybiliary cholangitis, portal hypertension, autoimmune disease (e.g., TypeI diabetes, ankylosing spondylitis, lupus, alopecia areata, rheumatoidarthritis, polymyalgia rheumatica, fibromyalgia, chronic fatiguesyndrome, Sjogren's syndrome, vitiligo, thyroiditis, vasculitis,urticarial (hives), Raynaud's syndrome), Schizophrenia, autism spectrumdisorders, hepatic encephlopathy, small intestitinal bacterialovergrowth, and chronic alcoholism, and the like.

In various preferred embodiments, the constipation to be treated is:associated with the use of a therapeutic agent; associated with aneuropathic disorder; post-surgical constipation (postoperative ileus);associated with a gastrointestinal tract disorder; idiopathic(functional constipation or slow transit constipation); associated withneuropathic, metabolic or endocrine disorder (e.g., diabetes mellitus,renal failure, hypothyroidism, hyperthyroidism, hypocalcaemia, MultipleSclerosis, Parkinson's disease, spinal cord lesions, neurofibromatosis,autonomic neuropathy, Chagas disease, Hirschsprung's disease or cysticfibrosis, and the like). Constipation may also be the result of surgery(postoperative ileus) or due the use of drugs such as analgesics (e.g.,opioids), antihypertensives, anticonvulsants, amidepressants,antispasmodics and antipsychotics.

In yet other embodiments, the constipation is associated with gastriculcers, infectious diarrhea, cancer (colorectal), “leaky gut syndrome”,cystic fibrosis gastrointestinal disease, multi-organ failure,microscopic colitis, necrotizing enterocolitis, atopy, food allergy,infections (respiratory), acute inflammation (e.g., sepsis, systemicinflammatory response syndrome), chronic inflammation (e.g., arthritis),obesity-induced metabolic diseases (e.g., nonalcoholic steatohepatitis,Type I diabetes, Type II diabetes, cardiovascular disease), kidneydisease, diabetic kidney disease, cirrhosis, nonalcoholicsteatohepatitis, nonalcoholic fatty acid liver disease, Steatosis,primary sclerosing cholangitis, primary biliary cholangitis, portalhypertension, autoimmune disease (e.g., Type I diabetes, ankylosingspondylitis, lupus, alopecia areata, rheumatoid arthritis, polymyalgiarheumatica, fibromyalgia, chronic fatigue syndrome, Sjogren's syndrome,vitiligo, thyroiditis, vasculitis, urticarial (hives), Raynaud'ssyndrome), Schizophrenia, autism spectrum disorders, hepaticencephlopathy, small intestitinal bacterial overgrowth, and chronicalcoholism, and the like.

Accordingly, it is to be noted that the present disclosure is furtherdirected to methods of treatment involving the administration of thecompound of the present disclosure, or a pharmaceutical compositioncomprising such a compound. Such methods may include, for example, amethod for increasing gastrointestinal motility in a patient, the methodcomprising administering to the patient a substantially non-permeable orsubstantially non-bioavailable NHE-inhibiting compound, or apharmaceutical composition comprising it. Additionally, oralternatively, the method may be for decreasing the activity of anintestinal NHE transporter in a patient, the method comprisingadministering to the patient a substantially non-permeable orsubstantially non-bioavailable NHE-inhibiting compound, or apharmaceutical composition comprising it. Additionally, oralternatively, the method may be for treating a gastrointestinal tractdisorder, a gastrointestinal motility disorder, irritable bowelsyndrome, chronic calcium-induced constipation in osteoporotic patients,chronic constipation occurring in cystic fibrosis patients, chronicconstipation occurring in chronic kidney disease patients, a functionalgastrointestinal tract disorder, gastroesophageal reflux disease,functional heartburn, dyspepsia, functional dyspepsia, non-ulcerdyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, colonicpseudo-obstruction, Crohn's disease, ulcerative colitis, inflammatorybowel disease, the method comprising administering an antagonist of theintestinal NHE, and more specifically, a substantially non-permeable orsubstantially non-bioavailable NHE-inhibiting compound, or apharmaceutical composition comprising it, either orally or by rectalsuppository. Additionally, or alternatively, the method may be fortreating or reducing pain, including visceral pain, pain associated witha gastrointestinal tract disorder or pain associated with some otherdisorder, the method comprising administering to a patient asubstantially non-permeable or substantially non-bioavailableNHE-inhibiting compound, or a pharmaceutical composition comprising itAdditionally, or alternatively, the method may be for treatinginflammation, including inflammation of the gastrointestinal tract,e.g., inflammation associated with a gastrointestinal tract disorder orinfection or some other disorder, the method comprising administering toa patient a substantially non-permeable or substantiallynon-bioavailable NHE-inhibiting compound, or a pharmaceuticalcomposition comprising it.

3. Metabolic Disorders

A pharmaceutical composition or preparation that may be used inaccordance with the present disclosure for the treatment of variousmetabolic disorders including the treatment or reduction of type IIdiabetes mellitus (T2DM), metabolic syndrome, and/or symptoms associatedwith such disorders comprises, in general, the substantially impermeableor substantially systemically non-bioavailable NHE-inhibiting compoundof the present disclosure, as well as various other optional componentsas further detailed herein below (e.g., pharmaceutically acceptableexcipients, etc.). The compounds utilized in the treatment methods ofthe present disclosure, as well as the pharmaceutical compositionscomprising them, may accordingly be administered alone, or as part of atreatment protocol or regiment that includes the administration or useof other beneficial compounds (as further detailed elsewhere herein). Inanother embodiment, the pharmaceutical composition can be used to treatother metabolic diseases such as non-alcoholic steatohepatitis, diabetesType I and II, and cardiovascular diseases.

Obesity is becoming a worldwide epidemic. In the United States,approximately ⅔rds of the population is either overweight (body massindex [BMI] 25 to 29.9) or obese (BMI≥30) (Ogden, C L et al, “Prevalenceof overweight and obesity in the united states, 1999-2004” JAMA 2006,295, 1549-1555). Obesity is a major risk factor for the development ofdiabetes and related complications, including cardiovascular disease andchronic kidney disease (CKD). The prevalence of T2DM has increasedalarmingly in the United States. The American Diabetes Associated (ADA)estimates that more than 23 million U.S. adults aged 20 years or olderhave diabetes, with T2DM accounting for approximately 95% of thesecases. The World Health Organization (WHO) has put the number of personswith diabetes worldwide at approximately 170 million (Campbell, R. K.“Type 2 diabetes: where we are today: an overview of disease burden,current treatments, and treatment strategies” Journal of the AmericanPharmacists Association 2009, 49(5), S3-S9).

Obesity is also a major risk factor for the development of metabolicsyndrome, and subsequently the development of CKD. Metabolic syndrome,previously known as Syndrome X, the plurimetabolic syndrome, thedysmetabolic syndrome, and other names, consists of a clustering ofmetabolic abnormalities including abdominal obesity,hypertriglyceridemia, low levels of high-density lipoprotein (HDL)cholesterol, elevated blood pressure (BP), and elevations in fastingglucose or diabetes (Townsend, R. R. et al “Metabolic Syndrome,Components, and Cardiovascular Disease Prevalence in Chronic KidneyDisease: Findings from the Chronic Renal Insufficiency Cohort (CRIC)Study” American Journal of Nephrology 2011, 33, 477-484). Metabolicsyndrome is common in patients with CKD and an important risk factor forthe development and progression of CKD.

Hemodynamic factors appear to play a significant role in obesity-inducedrenal dysfunction. Hypertension, which is closely linked to obesity,appears to be a major cause of renal dysfunction in obese patients(Wahba, I. M. et al “Obesity and obesity-initiated metabolic syndrome:mechanistic links to chronic kidney disease” Clinical Journal of theAmerican Society of Nephrology 2007, 2, 550-562). Studies in animals andin humans have shown that obesity is associated with elevated glomerularFiltration rate (GFR) and increased renal blood flow. This likely occursbecause of afferent arteriolar dilation as a result of proximal saltreabsorption, coupled with efferent renal arteriolar vasoconstriction asa result of elevated angiotensin II levels. These effects may contributeto hyperfiltration, glomerulomegaly, and later focal glomerulosclerosis.Even though GFR is increased in obesity, urinary sodium excretion inresponse to a saline load is often delayed, and individuals exhibit anabnormal pressure natriuresis, indicating avid proximal tubular sodiumreabsorption. In addition, increased fat distribution can causeincreased intra-abdomial pressure, leading to renal vein compression,thus raising renal venous pressure and diminishing renal perfusion. Increased fat, through a variety of mechanisms, can cause elevated renalinterstitial fluid hydrostatic fluid and may stimulate renal sodiumretention the thereby contribute to hypertension (Wahba_2007).

In view of the above, there exists a need in the art for agents that candivert sodium and fluid from a subject via mechanisms that either avoidthe kidney, or do not depend upon normal kidney function. A subject withmetabolic disease, including T2DM, metabolic syndrome, and the like, isa human, but can also be an animal in need of treatment with a compoundof the disclosure, e.g., companion animals (e.g., dogs, cats, and thelike), farm animals (e.g., cows, pigs, horses and the like) andlaboratory animals (e.g., rats, mice, guinea pigs and the like).

The compounds utilized in the treatment methods of the presentdisclosure, as well as the pharmaceutical compositions comprising them,may accordingly be administered alone, or as part of a combinationtherapy or regimen that includes the administration or use of othertherapeutic compounds related to the treatment of metabolic disorderssuch as T2DM and metabolic syndrome. In some particular embodiments, theNHE-inhibiting compound, including any pharmaceutical compositioncomprising the compound, is administered with a fluid absorbing polymer.

3. Urinary Protein Excretion

The compounds described herein have been shown to reduce urinary protein(e.g. albumin) excretion in a dose-dependent manner. FIG. 2 illustratesthe effects of two NHE3 inhibitors, NHE3-1 and NHE3-2, a compound of thepresent disclosure, on urinary albumin excretion in rats. Accordingly,another aspect of the invention is directed to method for loweringurinary protein excretion in a mammal and disorders associated withelevated urinary protein excretion. The method comprises administeringto a mammal in need thereof a pharmaceutically effective amount of acompound or pharmaceutical composition of Formula I. In one embodiment,the method of treating a disorder associated with elevated urinaryprotein excretion comprises administering to a mammal in need thereof apharmaceutically effective amount of a compound Ia, Ib, Ic, Id, Ie, If,Ig, Ih, or Ii or a combination thereof. In one embodiment, the proteinis albumin.

B. Combination Therapies

1. Fluid Retention and/or Salt Overload Disorders

As previously noted, the compounds described herein can be used alone orin combination with other agents. For example, the compounds can beadministered together with a diuretic (i.e., High Ceiling LoopDiuretics, Benzothiadiazide Diuretics, Potassium Sparing Diuretics,Osmotic Diuretics), cardiac glycoside, ACE inhibitor, angiotensin-2receptor antagonist, aldosterone antagonist, aldosterone synthaseinhibitor, renin inhibitor, calcium channel blocker, beta blocker, alphablocker, central alpha agonist, vasodilator, blood thinner,anti-platelet agent, lipid-lowering agent, peroxisomeproliferator-activated receptor (PPAR) gamma agonist agent or compoundor with a fluid-absorbing polymer as more fully described below. Theagent can be covalently attached to a compound described herein or itcan be a separate agent that is administered together with orsequentially with a compound described herein in a combination therapy.

Combination therapy can be achieved by administering two or more agents,e.g., a substantially non-permeable or substantially systemicallynon-bioavailable NHE-inhibiting compound described herein and adiuretic, cardiac glycoside, ACE inhibitor, angiotensin-2 receptorantagonist, aldosterone antagonist, aldosterone synthase inhibitor,renin inhibitor, calcium channel blocker, beta blocker, alpha blocker,central alpha agonist, vasodilator, blood thinner, anti-platelet agentor compound, each of which is formulated and administered separately, orby administering two or more agents in a single formulation. Othercombinations are also encompassed by combination therapy. For example,two agents can be formulated together and administered in conjunctionwith a separate formulation containing a third agent. While the two ormore agents in the combination therapy can be administeredsimultaneously, they need not be. For example, administration of a firstagent (or combination of agents) can precede administration of a secondagent (or combination of agents) by minutes, hours, days, or weeks.Thus, the two or more agents can be administered within minutes of eachother or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other orwithin 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other orwithin 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases,even longer intervals are possible. While in many cases it is desirablethat the two or more agents used in a combination therapy be present inwithin the patient's body at the same time, this need not be so.

Combination therapy can also include two or more administrations of oneor more of the agents used in the combination. For example, if agent Xand agent Y are used in a combination, one could administer themsequentially in any combination one or more times, e.g., in the orderX-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc.

The compounds described herein can be used in combination therapy with adiuretic. Among the useful diuretic agents are, for example: HighCeiling Loop Diuretics [Furosemide (Lasix), Ethacrynic Acid (Edecrin),Bumetanide (Bumex)|, Benzothiadiazide Diuretics [Hydrochlorothiazide(Hydrodiuril), Chlorothiazide (Diuril), Clorthalidone (Hygroton),Benzthiazide (Aguapres), Bendroflumethiazide (Naturetin),Methyclothiazide (Aguatensen), Polythiazide (Renese), Indapamide(Lozol), Cyclothiazide (Anhydron), Hydroflumethiazide (Diucardin),Metolazone (Diulo), Qumethazone (Hydromox), Trichlormethiazide (Naqua)],Potassium Sparing Diuretics[Spironolactone (Aldactone), Triamterene(Dyrenium), Amiloride (Midamor)], and Osmotic Diuretics [Mannitol(Osmitrol)]. Diuretic agents in the various classes are known anddescribed in the literature.

Cardiac glycosides (cardenolides) or other digitalis preparations can beadministered with the compounds of the disclosure in co-therapy. Amongthe useful cardiac glycosides are, for example: Digitoxin (Crystodigin),Digoxin (Lanoxin) or Deslanoside (Cedilanid-D). Cardiac glycosides inthe various classes are described in the literature.

Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors) can beadministered with the compounds of the disclosure in co-therapy. Amongthe useful ACE inhibitors are, for example: Captopril (Capoten),Enalapril (Vasotec), Lisinopril (Prinivil). ACE inhibitors in thevarious classes are described in the literature.

Angiotensin-2 Receptor Antagonists (also referred to as AT₁-antagonistsor angiotensin receptor blockers, or ARB's) can be administered with thecompounds of the disclosure in co-therapy. Among the usefulAngiotensin-2 Receptor Antagonists are, for example: Candesartan(Atacand), Eprosartan (Teveten), Irbesartan (Avapro), Losartan (Cozaar),Telmisartan (Micardis), Valsartan (Diovan). Angiotensin-2 ReceptorAntagonists in the various classes are described in the literature.

Calcium channel blockers such as Amlodipine (Norvasc, Lotrel), Bepridil(Vascor), Diltiazem (Cardizem, Tiazac), Felodipine (Plendil), Nifedipine(Adalat, Procardia), Nimodipine (Nimotop), Nisoldipine (Sular),Verapamil (Calan, Isoptin, Verelan) and related compounds described in,for example, EP 625162B1, U.S. Pat. Nos. 5,364,842, 5,587,454,5,824,645, 5,859,186, 5,994,305, 6,087,091, 6,136,786, WO 93/13128 A1,EP 1336409 A1, EP 835126 A1, EP 835126 B1, U.S. Pat. Nos. 5,795,864,5,891,849, 6,054,429, WO 97/01351 A1, the entire contents of which areincorporated herein by reference for all relevant and consistentpurposes, can be used with the compounds of the disclosure.

Beta blockers can be administered with the compounds of the disclosurein co-therapy. Among the useful beta blockers are, for example:Acebutolol (Sectral), Atenolol (Tenormin), Betaxolol (Kerlone),Bisoprolol/hydrochlorothiazide (Ziac), Bisoprolol (Zebeta), Carteolol(Cartrol), Metoprolol (Lopressor, Toprol XL), Nadolol (Corgard),Propranolol (Inderal), Sotalol (Betapace), Timolol (Blocadren). Betablockers in the various classes are described in the literature.

PPAR gamma agonists such as thiazolidinediones (also called glitazones)can be administered with the compounds of the disclosure in co-therapy.Among the useful PPAR agonists are, for example: rosiglitazone(Avandia), pioglitazone (Actos) and rivoglitazone.

Aldosterone antagonists can be administered with the compounds of thedisclosure in co-therapy. Among the useful Aldosterone antagonists are,for example: eplerenone, spironolactone, and canrenone.

Renin inhibitor can be administered with the compounds of the disclosurein co-therapy. Among the useful Renin inhibitors is, for example:aliskiren.

Alpha blockers can be administered with the compounds of the disclosurein co-therapy. Among the useful Alpha blockers are, for example:Doxazosin mesylate (Cardura), Prazosin hydrochloride (Minipress).Prazosin and polythiazide (Minizide), Terazosin hydrochloride (Hytrin).Alpha blockers in the various classes are described in the literature.

Central alpha agonists can be administered with the compounds of thedisclosure in co-therapy. Among the useful Central alpha agonists are,for example: Clonidine hydrochloride (Catapres), Clonidine hydrochlorideand chlorthalidone (Clorpres, Combipres), Guanabenz Acetate (Wytensin),Guanfacine hydrochloride (Tenex), Methyldopa (Aldomet), Methyldopa andchlorothiazide (Aldochlor), Methyldopa and hydrochlorothiazide(Aldoril). Central alpha agonists in the various classes are describedin the literature.

Vasodilators can be administered with the compounds of the disclosure inco-therapy. Among the useful vasodilators are, for example: Isosorbidedinitrate (Isordil), Nesiritide (Natrecor), Hydralazine (Apresoline),Nitrates/nitroglycerin, Minoxidil (Loniten). Vasodilators in the variousclasses are described in the literature.

Blood thinners can be administered with the compounds of the disclosurein co-therapy. Among the useful blood thinners are, for example:Warfarin (Coumadin) and Heparin. Blood thinners in the various classesare described in the literature.

Anti-platelet agents can be administered with the compounds of thedisclosure in co-therapy. Among the useful anti-platelet agents are, forexample: Cyclooxygenase inhibitors (Aspirin), Adenosine diphosphate(ADP) receptor inhibitors [Clopidogrel (Plavix), Ticlopidine (Ticlid)],Phosphodiesterase inhibitors [Cilostazol (Pletal)], GlycoproteinIIB/IIIA inhibitors [Abciximab (ReoPro), Eptifibatide (Integrilin),Tirofiban (Aggrastat), Defibrotide], Adenosine reuptake inhibitors[Dipyridamole (Persantine)]. Anti-platelet agents in the various classesare described in the literature.

Lipid-lowering agents can be administered with the compounds of thedisclosure in co-therapy. Among the useful lipid-lowering agents are,for example: Statins (HMG CoA reductase inhibitors), |Atorvastatin(Lipitor), Fluvastatin (Lescol), Lovastatin (Mevacor, Altoprev),Pravastatin (Pravachol), Rosuvastatin Calcium (Crestor), Simvastatin(Zocor)j, Selective cholesterol absorption inhibitors [ezetimibe(Zetia)], Resins (bile acid sequestrant or bile acid-binding drugs)[Cholestyramine (Questran, Questran Light, Prevalite, Locholest,Locholest Light), Colestipol (Colestid), Colesevelam Hcl (WelChol)],Fibrates (Fibric acid derivatives) [Gemfibrozil (Lopid), Fenofibrate(Antara, Lolibra, Tricor, and Triglide), Clofibrate (Atromid-S)], Niacin(Nicotinic acid). Lipid-lowering agents in the various classes aredescribed in the literature.

The compounds of the disclosure can be used in combination with peptidesor peptide analogs that activate the Guanylate Cyclase-receptor in theintestine and results in elevation of the intracellular secondmessenger, or cyclic guanosine monophosphate (cGMP), with increasedchloride and bicarbonate secretion into the intestinal lumen andconcomitant fluid secretion. Example of such peptides are Linaclotide(MD-1100 Acetate), endogenous hormones guanylin and uroguanylin andenteric bacterial peptides of the heat stable enterotoxin family (STpeptides) and those described in U.S. Pat. Nos. 5,140,102, 5,489,670,5,969,097, WO 2006/001931A2, WO 2008/002971A2, WO 2008/106429A2, US2008/0227685A1 and U.S. Pat. No. 7,041,786, the entire contents of whichare incorporated herein by reference for all relevant and consistentpurposes.

The compounds of the disclosure can be used in combination with type-2chloride channel agonists, such as Amitiza (Lubiprostone) and otherrelated compounds described in U.S. Pat. No. 6,414,016, the entirecontents of which are incorporated herein by reference for all relevantand consistent purposes.

The compounds described herein can be used in combination therapy withagents used for the treatment of obesity, T2DM, metabolic syndrome andthe like. Among the useful agents include: insulin; insulinsecretagogues, such as sulphonylureas; glucose-lowering effectors, suchas metformin; activators of the peroxisome proliferator-activatedreceptor γ (PPARγ), such as the thiazolidinediones; incretin-basedagents including dipeptidyl peptidase-4 inhibitors such as sitagliptin,and synthetic incretin mimetics such as liraglutide and exenatide;alpha-glucosidase inhibitors, such as acarbose; glinides, such asrepaglinide and nateglinide, and the like.

The compounds of the disclosure can be used in combination with P2Y2receptor agonists, such as those described in EP 1196396B1 and U.S. Pat.No. 6,624,150, the entire contents of which are incorporated herein byreference for all relevant and consistent purposes.

Other agents include natriuretic peptides such as nesiritide, arecombinant form of brain-natriuretic peptide (BNP) and anatrial-natriuretic peptide (ANP). Vasopressin receptor antagonists suchas tolvaptan and conivaptan may be co-administered as well as phosphatebinders such as renagel, renleva, phoslo and fosrenol. Other agentsinclude phosphate transport inhibitors (as described in U.S. Pat. Nos.4,806,532; 6,355,823; 6,787,528; 7,119,120; 7,109,184; U.S. Pat. Pub.No. 2007/021509; 2006/0280719; 2006/0217426; International Pat. Pubs. WO2001/005398, WO 2001/087294, WO 2001/082924, WO 2002/028353, WO2003/048134, WO 2003/057225, WO2003/080630, WO 2004/085448, WO2004/085382; European Pat. Nos. 1465638 and 1485391; and JP Patent No.2007131532, or phosphate transport antagonists such as Nicotinamide.

2. Gastrointestinal Tract Disorders

As previously noted, the compounds described herein can be used alone orin combination with other agents. For example, the compounds can beadministered together with an analgesic peptide or compound. Theanalgesic peptide or compound can be covalently attached to a compounddescribed herein or it can be a separate agent that is administeredtogether with or sequentially with a compound described herein in acombination therapy.

Combination therapy can be achieved by administering two or more agents,e.g., a substantially non-permeable or substantially non-bioavailableNHE-inhibiting compound described herein and an analgesic peptide orcompound, each of which is formulated and administered separately, or byadministering two or more agents in a single formulation. Othercombinations are also encompassed by combination therapy. For example,two agents can be formulated together and administered in conjunctionwith a separate formulation containing a third agent. While the two ormore agents in the combination therapy can be administeredsimultaneously, they need not be. For example, administration of a firstagent (or combination of agents) can precede administration of a secondagent (or combination of agents) by minutes, hours, days, or weeks.Thus, the two or more agents can be administered within minutes of eachother or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other orwithin 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other orwithin 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases,even longer intervals are possible. While in many cases it is desirablethat the two or more agents used in a combination therapy be present inwithin the patient's body at the same time, this need not be so.

Combination therapy can also include two or more administrations of oneor more of the agents used in the combination. For example, if agent Xand agent Y are used in a combination, one could administer themsequentially in any combination one or more times, e.g., in the orderX-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc.

The compounds described herein can be used in combination therapy withan analgesic agent, e.g., an analgesic compound or an analgesic peptide.The analgesic agent can optionally be covalently attached to a compounddescribed herein. Among the useful analgesic agents are, for example: Cachannel blockers, 5HT3 agonists (e.g., MCK-733), 5HT4 agonists (e.g.,tegaserod, prucalopride), and 5HT1 receptor antagonists, opioid receptoragonists (loperamide, fedotozine, and fentanyl), NK1 receptorantagonists, CCK receptor agonists (e.g., loxiglumide), NK1 receptorantagonists, NK3 receptor antagonists, norepinephrine-serotonin reuptakeinhibitors (NSR1), vanilloid and cannabanoid receptor agonists, andsialorphin. Analgesics agents in the various classes are described inthe literature.

Opioid receptor antagonists and agonists can be administered with thecompounds of the disclosure in co-therapy or linked to the compound ofthe disclosure, e.g., by a covalent bond. For example, opioid receptorantagonists such as naloxone, naltrexone, methyl nalozone, nalmefene,cypridime, beta funaltrexamine, naloxonazine, naltrindole, andnor-binaltorphimine are thought to be useful in the treatment ofopioid-induced constipaption (OIC). It can be useful to formulate opioidantagonists of this type in a delayed or sustained release formulation,such that initial release of the antagonist is in the mid to distalsmall intestine and/or ascending colon. Such antagonists are describedin U.S. Pat. No. 6,734,188 (WO 01/32180 A2), the entire contents ofwhich are incorporated herein by reference for all relevant andconsistent purposes. Enkephalin pentapeptide (HOE825;Tyr-D-Lys-Gly-Phe-L-homoserine) is an agonist of the μ- and γ-opioidreceptors and is thought to be useful for increasing intestinal motility(Eur. J. Pharm., 219:445, 1992), and this peptide can be used inconjunction with the compounds of the disclosure. Also useful istrimebutine which is thought to bind to mu/delta/kappa opioid receptorsand activate release of motilin and modulate the release of gastrin,vasoactive intestinal peptide, gastrin and glucagons. K-opioid receptoragonists such as fedotozine, ketocyclazocine, and compounds described inUS 2005/0176746 (WO 03/097051 A2), the entire contents of which areincorporated herein by reference for all relevant and consistentpurposes, can be used with or linked to the compounds of the disclosure.In addition, μ-opioid receptor agonists, such as morphine,diphenyloxylate, frakefamide (H-Tyr-D-Ala-Phe(F)-Phe-NH₂, disclosed inWO 01/019849 A1, the entire contents of which are incorporated herein byreference for all relevant and consistent purposes) and loperamide canbe used.

Tyr-Arg (kyotorphin) is a dipeptide that acts by stimulating the releaseof met-enkephalins to elicit an analgesic effect (J. Biol. Chem.262:8165, 1987). Kyotorphin can be used with or linked to the compoundsof the disclosure. CCK receptor agonists such as caerulein fromamphibians and other species are useful analgesic agents that can beused with or linked to the compounds of the disclosure.

Conotoxin peptides represent a large class of analgesic peptides thatact at voltage gated Ca channels, NMDA receptors or nicotinic receptors.These peptides can be used with or linked to the compounds of thedisclosure.

Peptide analogs of thymulin (U.S. Pat. No. 7,309,690 or FR 2830451, theentire contents of which are incorporated herein by reference for allrelevant and consistent purposes) can have analgesic activity and can beused with or linked to the compounds of the disclosure.

CCK (CCKa or CCKb) receptor antagonists, including loxiglumide anddexloxiglumide (the R-isomer of loxiglumide) (U.S. Pat. No. 5,130,474 orWO 88/05774, the entire contents of which are incorporated herein byreference for all relevant and consistent purposes) can have analgesicactivity and can be used with or linked to the compounds of thedisclosure.

Other useful analgesic agents include 5-HT4 agonists such astegaserod/zelnorm and lirexapride. Such agonists are described in:EP1321142 A1, WO 03/053432A], EP 505322 A1, EP 505322 BI, EP 507672 A1,EP 507672 BI, U.S. Pat. Nos. 5,510,353 and 5,273,983, the entirecontents of which are incorporated herein by reference for all relevantand consistent purposes.

Calcium channel blockers such as zicyanotide and related compoundsdescribed in, for example, EP 625162B1, U.S. Pat. Nos. 5,364,842,5,587,454, 5,824,645, 5,859,186, 5,994,305, 6,087,091, 6,136,786, WO93/13128 A1, EP 1336409 A1, EP 835126 A1, EP 835126 BI, U.S. Pat. Nos.5,795,864, 5,891,849, 6,054,429, WO 97/0135 A1, the entire contents ofwhich are incorporated herein by reference for all relevant andconsistent purposes, can be used with or linked to the compounds of thedisclosure.

Various antagonists of the NK-1, NK-2, and NK-3 receptors (for a reviewsee Giardina et al. 2003 Drugs 6:758) can be can be used with or linkedto the compounds of the disclosure.

NK1 receptor antagonists such as: aprepitant (Merck & Co Inc),vofopitant, ezlopitant (Pfizer, Inc.), R-673 (Hoffmann-La Roche Ltd),SR-14033 and related compounds described in, for example, EP 873753 A1,U.S. 20010006972 A1, U.S. 20030109417 A1, WO 01/52844 A1, the entirecontents of which are incorporated herein by reference for all relevantand consistent purposes, can be used with or linked to the compounds ofthe disclosure.

NK-2 receptor antagonists such as nepadutant (Menarini Ricerche SpA),saredutant (Sanofi-Synthelabo), SR-144190 (Sanofi-Synthelabo) andUK-290795 (Pfizer Inc) can be used with or linked to the compounds ofthe disclosure.

NK3 receptor antagonists such as osanetant (Sanofi-Synthelabo),talnetant and related compounds described in, for example, WO 02/094187A2, EP 876347 A1, WO 97/21680 A1, U.S. Pat. No. 6,277,862, WO 98/11090,WO 95/28418, WO 97/19927, and Boden et al. (J Med. Chem. 39:1664-75,1996), the entire contents of which are incorporated herein by referencefor all relevant and consistent purposes, can be used with or linked tothe compounds of the disclosure.

Norepinephrine-serotonin reuptake inhibitors such as milnacipran andrelated compounds described in WO 03/077897 A1, the entire contents ofwhich are incorporated herein by reference for all relevant andconsistent purposes, can be used with or linked to the compounds of thedisclosure.

Vanilloid receptor antagonists such as arvanil and related compoundsdescribed in WO 01/64212 A1, the entire contents of which areincorporated herein by reference for all relevant and consistentpurposes, can be used with or linked to the compounds of the disclosure.

The compounds can be used in combination therapy with aphosphodiesterase inhibitor (examples of such inhibitors can be found inU.S. Pat. No. 6,333,354, the entire contents of which are incorporatedherein by reference for all relevant and consistent purposes).

The compounds can be used alone or in combination therapy to treatdisorders associated with chloride or bicarbonate secretion that maylead to constipation, e.g., Cystic Fibrosis.

The compounds can also or alternatively be used alone or in combinationtherapy to treat calcium-induced constipation effects. Constipation iscommonly found in the geriatric population, particularly patients withosteoporosis who have to take calcium supplements. Calcium supplementshave shown to be beneficial in ostoporotic patients to restore bonedensity but compliance is poor because of constipation effectsassociated therewith.

The compounds of the current disclosure have can be used in combinationwith an opioid. Opioid use is mainly directed to pain relief, with anotable side-effect being GI disorder, e.g. constipation. These agentswork by binding to opioid receptors, which are found principally in thecentral nervous system and the gastrointestinal tract. The receptors inthese two organ systems mediate both the beneficial effects, and theundesirable side effects (e.g. decrease of gut motility and ensuingconstipation). Opioids suitable for use typically belong to one of thefollowing exemplary classes: natural opiates, alkaloids contained in theresin of the opium poppy including morphine, codeine and thebaine;semi-synthetic opiates, created from the natural opioids, such ashydromorphone, hydrocodone, oxycodone, oxymorphone, desomorphine,diacetylmorphine (Heroin), nicomorphine, dipropanoylmorphine,benzylmorphine and ethylmorphine; fully synthetic opioids, such asfentanyl, pethidine, methadone, tramadol and propoxyphene; endogenousopioid peptides, produced naturally in the body, such as endorphins,enkephalins, dynorphins, and endomorphins.

The compound of the disclosure can be used alone or in combinationtherapy to alleviate GI disorders encountered with patients with renalfailure (stage 3-5). Constipation is the second most reported symptom inthat category of patients (Murtagh et al., 2006; Murtagh et al., 2007a;Murtagh et al., 2007b). Without being held by theory, it is believedthat kidney failure is accompanied by a stimulation of intestinal Nare-absorption (Hatch and Freel, 2008). A total or partial inhibition ofsuch transport by administration of the compounds of the disclosure canhave a therapeutic benefit to improve GI transit and relieve abdominalpain. In that context, the compounds of the disclosure can be used incombination with Angiotensin-modulating agents: Angiotensin ConvertingEnzyme (ACE) inhibitors (e.g. captopril, enalopril, lisinopril,ramipril) and Angiotensin II receptor antagonist therapy (also referredto as AT₁-antagonists or angiotensin receptor blockers, or ARB's);diuretics such as loop diuretics (e.g. furosemide, bumetanide), Thiazidediuretics (e.g. hydrochlorothiazide, chlorthalidone, chlorthiazide) andpotassium-sparing diuretics: amiloride; beta blockers: bisoprolol,carvedilol, nebivolol and extended-release metoprolol; positiveinotropes: Digoxin, dobutamine; phosphodiesterase inhibitors such asmilrinone; alternative vasodilators: combination of isosorbidedinitrate/hydralazine; aldosterone receptor antagonists: spironolactone,eplerenone; natriuretic peptides: Nesiritide, a recombinant form ofbrain-natriuretic peptide (BNP), atrial-natriuretic peptide (ANP);vasopressin receptor antagonists: Tolvaptan and conivaptan; phosphatebinder (Renagel, Renleva, Phoslo, Fosrenol); phosphate transportinhibitor such as those described in U.S. Pat. Nos. 4,806,532,6,355,823, 6,787,528, WO 2001/005398, WO 2001/087294, WO 2001/082924, WO2002/028353, WO 2003/048134, WO 2003/057225, U.S. Pat. No. 7,119,120, EP1465638, US Appl. 2007/021509, WO 2003/080630, U.S. Pat. No. 7,109,184,US Appl. 2006/0280719, EP 1485391, WO 2004/085448, WO 2004/085382, USAppl. 2006/0217426, JP 2007/131532, the entire contents of which areincorporated herein by reference for all relevant and consistentpurposes, or phosphate transport antagonist (Nicotinamide).

The compounds of the disclosure can be used in combination with peptidesor peptide analogs that activate the Guanylate Cyclase-receptor in theintestine and results in elevation of the intracellular secondmessenger, or cyclic guanosine monophosphate (cGMP), with increasedchloride and bicarbonate secretion into the intestinal lumen andconcomitant fluid secretion. Example of such peptides are Linaclotide(MD-1100 Acetate), endogenous hormones guanylin and uroguanylin andenteric bacterial peptides of the heat stable enterotoxin family (STpeptides) and those described in U.S. Pat. Nos. 5,140,102, 5,489,670,5,969,097, WO 2006/001931A2, WO 2008/002971 A2, WO 2008/106429A2, US2008/0227685A1 and U.S. Pat. No. 7,041,786, the entire contents of whichare incorporated herein by reference for all relevant and consistentpurposes.

The compounds of the disclosure can be used in combination with type-2chloride channel agonists, such as Amitiia (Lubiprostone) and otherrelated compounds described in U.S. Pat. No. 6,414,016, the entirecontents of which are incorporated herein by reference for all relevantand consistent purposes.

The compounds of the disclosure can be used in combination with P2Y2receptor agonists, such as those described in EP 1196396B1 and U.S. Pat.No. 6,624,150, the entire contents of which are incorporated herein byreference for all relevant and consistent purposes.

The compounds of the disclosure can be used in combination with laxativeagents such as bulk-producing agents, e.g. psyllium husk (Metamucil),methylcellulose (Citrucel), polycarbophil, dietary fiber, apples, stoolsofteners/surfactant such as docusate (Colace, Diocto); hydrating agents(osmotics), such as dibasic sodium phosphate, magnesium citrate,magnesium hydroxide (Milk of magnesia), magnesium sulfate (which isEpsom salt), monobasic sodium phosphate, sodium biphosphate;hyperosmotic agents: glycerin suppositories, sorbitol, lactulose, andpolyethylene glycol (PEG). The compounds of the disclosure can be alsobe used in combination with agents that stimulate gut peristalsis, suchas Bisacodyl tablets (Dulcolax), Casanthranol, Senna and Aloin, fromAloe Vera.

In one embodiment, the compounds of the disclosure accelerategastrointestinal transit, and more specifically in the colon, withoutsubstantially affecting the residence time in the stomach, i.e. with nosignificant effect on the gastric emptying time. Even more specificallythe compounds of the invention restore colonic transit without theside-effects associated with delayed gastric emptying time, such asnausea. The GI and colonic transit are measured in patients usingmethods reported in, for example: Burton D D, Camilleri M, Mullan B P,et al., J. Nucl. Med., 1997; 38:1807-1810; Cremonini F, Mullan B P,Camilleri M, et al., Aliment. Pharmacol. Ther., 2002; 16:1781-1790;Camilleri M, Zinsmeister A R, Gastroenterology, 1992; 103:36-42; BourasE P, Camilleri M, Burton D D, et al., Gastroenterology, 2001;120:354-360; Coulie B, Szarka L A, Camilleri M, et al.,Gastroenterology, 2000; 119:41-50; Prather C M, Camilleri M, ZinsmeisterA R, et al., Gastroenterology, 2000; 118:463-468; and, Camilleri M,McKinzie S, Fox J, et al., Clin. Gastroenterol. Hepatol., 2004;2:895-904.

C. Polymer Combination Therapy

The NHE-inhibiting compounds described therein may be administered topatients in need thereof in combination with a fluid-absorbing polymer(“FAP”). The intestinal fluid-absorbing polymers useful foradministration in accordance with embodiments of the present disclosuremay be administered orally in combination with non-absorbableNHE-inhibiting compounds (e.g., a NHE-3 inhibitor) to absorb theintestinal fluid resulting from the action of the sodium transportinhibitors. Such polymers swell in the colon and bind fluid to impart aconsistency to stools that is acceptable for patients. Thefluid-absorbing polymers described herein may be selected from polymerswith laxative properties, also referred to as bulking agents (i.e.,polymers that retain some of the intestinal fluid in the stools andimpart a higher degree of hydration in the stools and facilitatetransit). The fluid-absorbing polymers may also be optionally selectedfrom pharmaceutical polymers with anti-diarrhea function, i.e., agentsthat maintain some consistency to the stools to avoid watery stools andpotential incontinence.

The ability of the polymer to maintain a certain consistency in stoolswith a high content of fluid can be characterized by its “water holdingpower.” Wenzl et al. (in Determinants of decreased fecal consistency inpatients with diarrhea; Gastroenterology, v. 108, no. 6, p. 1729-1738(1995)) studied the determinants that control the consistency of stoolsof patients with diarrhea and found that they were narrowly correlatedwith the water holding power of the feces. The water holding power isdetermined as the water content of given stools to achieve a certainlevel of consistency (corresponding to “formed stool” consistency) afterthe reconstituted fecal matter has been centrifuged at a certain gnumber. Without being held to any particular theory, has been found thatthe water holding power of the feces is increased by ingestion ofcertain polymers with a given fluid absorbing profile. Morespecifically, it has been found that the water-holding power of saidpolymers is correlated with their fluid absorbency under load (AUL);even more specifically the AUL of said polymers is greater than 15 g ofisotonic fluid/g of polymer under a static pressure of 5 kPa, or under astatic pressure of 10 kPa.

The FAP utilized in the treatment method of the present disclosure alsohas a AUL of at least about 10 g, about 15 g, about 20 g, about 25 g ormore of isotonic fluid/g of polymer under a static pressure of about 5kPa, or about 10 kPA, and may have a fluid absorbency of about 20 g,about 25 g or more, as determined using means generally known in theart. Additionally or alternatively, the FAP may impart a minimumconsistency to fecal matter and, in some embodiments, a consistencygraded as “soft” in the scale described in the test method below, whenfecal non water-soluble solid fraction is from 10% to 20%, and thepolymer concentration is from 1% to 5% of the weight of stool. Thedetermination of the fecal non water-soluble solid fraction of stools isdescribed in Wenz et al. The polymer may be uncharged or may have a lowcharge density (e.g., 1-2 meq/gr). Alternatively or in addition, thepolymer may be delivered directly to the colon using known deliverymethods to avoid premature swelling in the esophagus.

In one embodiment of the present disclosure, the FAP is a“superabsorbent” polymer (i.e., a lightly crosslinked, partiallyneutralized polyelectrolyte hydrogel similar to those used in babydiapers, feminine hygiene products, agriculture additives, etc.).Superabsorbent polymers may be made of a lightly crosslinkedpolyacrylate hydrogel. The swelling of the polymer is driven essentiallyby two effects: (i) the hydration of the polymer backbone and entropy ofmixing and (ii) the osmotic pressure arising from the counter-ions(e.g., Na ions) within the gel. The gel swelling ratio at equilibrium iscontrolled by the elastic resistance inherent to the polymer network andby the chemical potential of the bathing fluid, i.e., the gel willde-swell at higher salt concentration because the background electrolytewill reduce the apparent charge density on the polymer and will reducethe difference of free ion concentrations inside and outside the gelthat drives osmotic pressure. The swelling ratio SR (g of fluid per g ofdry polymer and synonymously “fluid absorbency”) may vary from 1000 inpure water down to 30 in 0.9% NaCl solution representative ofphysiological saline (i.e., isotonic). SR may increase with the degreeof neutralization and may decrease with the crosslinking density. SRgenerally decreases with an applied load with the extent of reductiondependent on the strength of the gel, i.e., the crosslinking density.The salt concentration within the gel, as compared with the externalsolution, may be lower as a result of the Donnan effect due to theinternal electrical potential.

The fluid-absorbing polymer may include crosslinked polyacrylates whichare fluid absorbent such as those prepared from α,β-ethylenicallyunsaturated monomers, such as monocarboxylic acids, polycarboxylicacids, acrylamide and their derivatives. These polymers may haverepeating units of acrylic acid, methacrylic acid, metal salts ofacrylic acid, acrylamide, and acrylamide derivatives (such as2-acrylamido-2-methylpropanesulfonic acid) along with variouscombinations of such repeating units as copolymers. Such derivativesinclude acrylic polymers which include hydrophilic grafts of polymerssuch as polyvinyl alcohol. Examples of suitable polymers and processes,including gel polymerization processes, for preparing such polymers aredisclosed in U.S. Pat. Nos. 3,997,484; 3,926,891; 3,935,099; 4,090,013;4,093,776; 4,340,706; 4,446,261; 4,683,274; 4,459,396; 4,708,997;4,076,663; 4,190,562; 4,286,082; 4,857,610; 4,985,518; 5,145,906;5,629,377 and 6,908,609 which are incorporated herein by reference forall relevant and consistent purposes (in addition, see Buchholz, F. L.and Graham, A. T., “Modern Superabsorbent Polymer Technology,” JohnWiley & Sons (1998), which is also incorporated herein by reference forall relevant and consistent purposes). A class of preferred polymers fortreatment in combination with NHE-inhibitors is polyelectrolytes.

The degree of crosslinking can vary greatly depending upon the specificpolymer material; however, in most applications the subjectsuperabsorbent polymers are only lightly crosslinked, that is, thedegree of crosslinking is such that the polymer can still absorb over 10times its weight in physiological saline (i.e., 0.9% saline). Forexample, such polymers typically include less than about 0.2 mole %crosslinking agent.

In some embodiments, the FAP's utilized for treatment are CalciumCarbophil (Registry Number: 9003-97-8, also referred as Carbopol EX-83),and Carpopol 934P.

In some embodiments, the fluid-absorbing polymer is prepared by highinternal phase emulsion (“HIPE”) processes. The HIPE process leads topolymeric foam slabs with a very large porous fraction of interconnectedlarge voids (about 100 microns) (i.e., open-cell structures). Thistechnique produces flexible and collapsible foam materials withexceptional suction pressure and fluid absorbency (see U.S. Pat. Nos.5,650,222; 5,763,499 and 6,107,356, which are incorporated herein forall relevant and consistent purposes). The polymer is hydrophobic and,therefore, the surface should be modified so as to be wetted by theaqueous fluid. This is accomplished by post-treating the foam materialby a surfactant in order to reduce the interfacial tension. Thesematerials are claimed to be less compliant to loads, i.e., less prone tode-swelling under static pressure.

In some embodiments, fluid-absorbing gels are prepared by aqueous freeradical polymerization of acrylamide or a derivative thereof, acrosslinker (e.g., methylene-bis-acrylamide) and a free radicalinitiator redox system in water. The material is obtained as a slab.Typically, the swelling ratio of crosslinked polyacrylamide at lowcrosslinking density (e.g., 2%-4% expressed as weight % ofmethylene-bis-acrylamide) is between 25 and 40 (F. Horkay,Macromolecules, 22, pp. 2007-09 (1989)). The swelling properties ofthese polymers have been extensively studied and are essentially thesame of those of crosslinked polyacrylic acids at high saltconcentration. Under those conditions, the osmotic pressure is null dueto the presence of counter-ions and the swelling is controlled by thefree energy of mixing and the network elastic energy. Stateddifferently, a crosslinked polyacrylamide gel of same crosslink densityas a neutralized polyacrylic acid will exhibit the same swelling ratio(i.e., fluid absorbing properties) and it is believed the same degree ofdeswelling under pressure, as the crosslinked polyelectrolyte at highsalt content (e.g., 1 M). The properties (e.g., swelling) of neutralhydrogels will not be sensitive to the salt environment as long as thepolymer remains in good solvent conditions. Without being held to anyparticular theory, it is believed that the fluid contained within thegel has the same salt composition than the surrounding fluid (i.e.,there is no salt partitioning due to Donnan effect).

Another subclass of fluid-absorbing polymers that may be utilized ishydrogel materials that include N-alkyl acrylamide polymers (e.g.,N-isopropylacrylamide (NIPAM)). The corresponding aqueous polyNIPAMhydrogel shows a temperature transition at about 35° C. Above thistemperature the hydrogel may collapse. The mechanism is generallyreversible and the gel re-swells to its original swelling ratio when thetemperature reverts to room temperature. This allows production ofnanoparticles by emulsion polymerization (R. Pelton, Advances in Colloidand Interface Science, 85, pp. 1-33, (2000)). The swellingcharacteristics of poly-NIPAM nanoparticles below the transitiontemperature have been reported and are similar to those reported forbulk gel of polyNIPAM and equivalent to those found for polyacrylamide(i.e. 30-50 g/g) (W. McPhee, Journal of Colloid and Interface Science,156, pp. 24-30 (1993); and, K. Oh, Journal of Applied Polymer Science,69, pp. 109-114 (1997)).

In some embodiments, the FAP utilized for treatment in combination witha NHE-inhibitor is a superporous gel that may delay the emptying of thestomach for the treatment of obesity (J. Chen, Journal of ControlledRelease, 65, pp. 73-82 (2000), or to deliver proteins.Polyacrylate-based SAP's with a macroporous structure may also be used.Macroporous SAP and superporous gels differ in that the porous structureremains almost intact in the dry state for superporous gels, butdisappears upon drying for macroporous SAP's. The method of preparationis different although both methods use a foaming agent (e.g., carbonatesalt that generates CO₂ bubbles during polymerization). Typical swellingratios, SR, of superporous materials are around 10. Superporous gelskeep a large internal pore volume in the dry state.

Macroporous hydrogels may also be formed using a method whereby polymerphase separation in induced by a non-solvent. The polymer may bepoly-NIPAM and the non-solvent utilized may be glucose (see, e.g., Z.Zhang, J. Org. Chem., 69, 23 (2004)) or NaCl (see, e.g., Cheng et al.,Journal of Biomedical Materials Research—Part A, Vol. 67, Issue 1, 1Oct. 2003, Pages 96-103). The phase separation induced by the presenceof NaCl leads to an increase in swelling ratio. These materials arepreferred if the swelling ratio of the material, SR, is maintained insalt isotonic solution and if the gels do not collapse under load. Thetemperature of “service” should be shifted beyond body temperature, e.g.by diluting NIPAM in the polymer with monomer devoid of transitiontemperature phenomenon.

In some embodiments, the fluid-absorbing polymer may be selected fromcertain naturally-occurring polymers such as those containingcarbohydrate moieties. In a preferred embodiment, suchcarbohydrate-containing hydrogels are non-digestible, have a lowfraction of soluble material and a high fraction of gel-formingmaterials. In some embodiments, the fluid-absorbing polymer is selectedfrom xanthan, guar, wellan, hemicelluloses, alkyl-cellulose,hydro-alkyl-cellulose, carboxy-alkyl-cellulose, carrageenan, dextran,hyaluronic acid and agarose. In a preferred embodiment, the gel formingpolymer is psyllium. Psyllium (or “ispaghula”) is the common name usedfor several members of the plant genus Plantago whose seeds are usedcommercially for the production of mucilage. The fluid-absorbing polymeris also in the gel-forming fraction of psyllium, i.e., a neutralsaccharide copolymer of arabinose (25%) and xylose (75%) ascharacterized in (J. Marlett, Proceedings of the Nutrition Society, 62,pp. 2-7-209 (2003); and, M. Fischer, Carbohydrate Research, 339,2009-2012 (2004)), and further described in U.S. Pat. Nos. 6,287,609;7,026,303; 5,126,150; 5,445,831; 7,014,862; 4,766,004; 4,999,200, eachof which is incorporated herein for all relevant and consistentpurposes, and over-the-counter psillium-containing agents such as thosemarketed under the name Metamucil (The Procter and Gamble company). Apsyllium-containing dosage form is also suitable for chewing, where thechewing action disintegrates the tablet into smaller, discrete particlesprior to swallowing but which undergoes minimal gelling in the mouth,and has acceptable mouthfeel and good aesthetics as perceived by thepatient.

The psyllium-containing dosage form includes physically discrete unitsuitable as a unitary dosage for human subjects and other mammals, eachcontaining a predetermined quantity of active material (e.g. thegel-forming polysaccharide) calculated to produce the desiredtherapeutic effect. Solid oral dosage forms that are suitable for thepresent compositions include tablets, pills, capsules, lozenges,chewable tablets, troches, cachets, pellets, wafer and the like.

In some embodiments, the FAP is a polysaccharide particle wherein thepolysaccharide component includes xylose and arabinose. The ratio of thexylose to the arabinose may be at least about 3:1 by weight, asdescribed in U.S. Pat. Nos. 6,287,609; 7,026,303 and 7,014,862, each ofwhich is incorporated herein for all relevant and consistent purposes.

The fluid-absorbing polymers described herein may be used in combinationwith the NHE-inhibiting compound or a pharmaceutical compositioncontaining it. The NHE-inhibiting compound and the FAP may also beadministered with other agents including those described under theheading “Combination Therapies” without departing from the scope of thepresent disclosure. As described above, the NHE-inhibiting compound maybe administered alone without use of a fluid-absorbing polymer toresolve symptoms without eliciting significant diarrhea or fecal fluidsecretion that would require the co-administration of a fluid-absorbingpolymer.

The fluid-absorbing polymers described herein may be selected so as tonot induce any substantial interaction with the NHE-inhibiting compoundor a pharmaceutical composition containing it. As used herein, “nosubstantial interaction” generally means that the co-administration ofthe FAP polymer would not substantially alter (i.e., neithersubstantially decrease nor substantially increase) the pharmacologicalproperty of the NHE-inhibiting compounds administered alone. Forexample, FAPs containing negatively charged functionality, such ascarboxylates, sulfonates, and the like, may potentially interactionically with positively charged NHE-inhibiting compounds, preventingthe inhibitor from reaching its pharmacological target. In addition, itmay be possible that the shape and arrangement of functionality in a FAPcould act as a molecular recognition element, and sequestorNHE-inhibiting compounds via “host-guest” interactions via therecognition of specific hydrogen bonds and/or hydrophobic regions of agiven inhibitor. Accordingly, in various embodiments of the presentdisclosure, the FAP polymer may be selected, for co-administration oruse with a compound of the present disclosure, to ensure that (i) itdoes not ionically interact with or bind with the compound of thepresent disclosure (by means of, for example, a moiety present thereinpossessing a charge opposite that of a moiety in the compound itself),and/or (ii) it does not possess a charge and/or structural conformation(or shape or arrangement) that enables it to establish a “host-guest”interaction with the compound of the present disclosure (by means of,for example, a moiety present therein that may act as a molecularrecognition element and sequester the NHE inhibitor or inhibiting moietyof the compound).

D. Dosage

It is to be noted that, as used herein, an “effective amount” (or“pharmaceutically effective amount”) of a compound disclosed herein, isa quantity that results in a beneficial clinical outcome of thecondition being treated with the compound compared with the absence oftreatment. The amount of the compound or compounds administered willdepend on the degree, severity, and type of the disease or condition,the amount of therapy desired, and the release characteristics of thepharmaceutical formulation. It will also depend on the subject's health,size, weight, age, sex and tolerance to drugs. Typically, the compoundis administered for a sufficient period of time to achieve the desiredtherapeutic effect.

In embodiments wherein both an NHE-inhibitor compound and afluid-absorbing polymer are used in the treatment protocol, theNHE-inhibiting compound and FAP may be administered together or in a“dual-regimen” wherein the two therapeutics are dosed and administeredseparately. When the NHE-inhibiting compound and the fluid-absorbingpolymer are dosed separately, the typical dosage administered to thesubject in need of the NHE-inhibiting compound is typically from about 5mg per day and about 5000 mg per day and, in other embodiments, fromabout 50 mg per day and about 1000 mg per day. Such dosages may inducefecal excretion of sodium (and its accompanying anions), from about 10mmol up to about 250 mmol per day, from about 20 mmol to about 70 mmolper day or even from about 30 mmol to about 60 mmol per day.

The typical dose of the fluid-absorbing polymer is a function of theextent of fecal secretion induced by the non-absorbable NHE-inhibitingcompound. Typically, the dose is adjusted according to the frequency ofbowel movements and consistency of the stools. More specifically thedose is adjusted so as to avoid liquid stools and maintain stoolconsistency as “soft” or semi-formed, or formed. To achieve the desiredstool consistency and provide abdominal relief to patients, typicaldosage ranges of the fluid-absorbing polymer to be administered incombination with the NHE-inhibiting compound, are from about 2 g toabout 50 g per day, from about 5 g to about 25 g per day or even fromabout 10 g to about 20 g per day. When the NHE-inhibiting compound andthe FAP are administered as a single dosage regimen, the daily uptakemay be from about 2 g to about 50 g per day, from about 5 g to about 25g per day, or from about 10 g to about 20 g per day, with a weight ratioof NHE-inhibiting compound to fluid-absorbing polymer being from about1:1000 to 1:10 or even from about 1:500 to 1:5 or about 1:100 to 1:5.

A typical dosage of the substantially impermeable or substantiallysystemically non-bioavailable, NHE-inhibiting compound when used alonewithout a FAP may be between about 0.2 mg per day and about 2 g per day,or between about 1 mg and about 1 g per day, or between about 5 mg andabout 500 mg, or between about 10 mg and about 250 mg per day, which isadministered to a subject in need of treatment.

The frequency of administration of therapeutics described herein mayvary from once-a-day (QD) to twice-a-day (BID) or thrice-a-day (TID),etc., the precise frequency of administration varying with, for example,the patient's condition, the dosage, etc. For example, in the case of adual-regimen, the NHE-inhibiting compound could be taken once-a-daywhile the fluid-absorbing polymer could be taken at each meal (TID).Furthermore, as disclosed in U.S. Application No. 61/584,753 filed Jan.9, 2012, the NHE-inhibiting compound is administered twice-a-day (BID),or thrice-a-day (TID), and in a more specific embodiment, theNHE-inhibiting compound is administered in an amount ranging from 2-200mg per dose BID, or 2-100 mg per dose TID. In more specific embodiments,the NHE-inhibiting compound is administered in an amount of about 15 mgper dose, about 30 mg per dose, or about 45 mg per dose, and in a morespecific embodiment, in an amount of 15 mg per dose, 30 mg per dose, or45 mg per dose.

E. Modes of Administration

The substantially impermeable or substantially systemicallynon-bioavailable NHE-inhibiting compounds of the present disclosure withor without the fluid-absorbing polymers described herein may beadministered by any suitable route. The compound is administrated orally(e.g., dietary) in capsules, suspensions, tablets, pills, dragees,liquids, gels, syrups, slurries, and the like. Methods for encapsulatingcompositions (such as in a coating of hard gelatin or cyclodextran) areknown in the art (Baker, et al., “Controlled Release of BiologicalActive Agents”, John Wiley and Sons, 1986). The compounds can beadministered to the subject in conjunction with an acceptablepharmaceutical carrier as part of a pharmaceutical composition. Theformulation of the pharmaceutical composition will vary according to theroute of administration selected. Suitable pharmaceutical carriers maycontain inert ingredients which do not interact with the compound. Thecarriers are biocompatible, i.e., non-toxic, non-inflammatory,non-immunogenic and devoid of other undesired reactions at theadministration site. Examples of pharmaceutically acceptable carriersinclude, for example, saline, commercially available inert gels, orliquids supplemented with albumin, methyl cellulose or a collagenmatrix. Standard pharmaceutical formulation techniques can be employed,such as those described in Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa.

In other embodiments, the NHE-3 inhibiting compounds may be systemicallyadministered. In one embodiment, the compounds of the present inventionare administered systemically to inhibit NHE-3 in the kidney. Withoutbeing held to any particular theory, the impermeable NHE-inhibitingcompounds (e.g., NHE-3, -2 and/or -8 inhibitors) of the presentdisclosure can also be administered parenterally, by intravenous,subcutaneous or intramuscular injection or infusion to inhibit NHE3 inthe kidney. NHE3 is expressed at high levels on the apical surface ofthe proximal tubule of the kidney and couples luminal Na reabsorption tothe secretion of intracellular protons. Since NHE3 accounts forapproximately 60-80% of sodium reabsorption in the kidney, it isanticipated that NHE inhibition could permit the removal of substantialquantities of systemic fluid and sodium to prevent edema and resolvecongestive heart failure symptoms. This effect could be achieved by NHEinhibition in combination with other diuretics, specifically loopdiuretics, like furosemide, to inhibit tubuloglomerular feedback. Inaddition, since sodium reabsorption via NHE3 in the proximal tubule isresponsible for a large proportion of the energy requirement of theproximal tubule cell, it is anticipated that NHE inhibition in thekidney could be beneficial by reducing the energy requirement andprotecting the proximal tubule cell in settings of decreased energyavailability to the proximal tubule, such as those that occur as aresult of kidney hypoxia such as in kidney ischemia reperfusion injuryresulting in acute kidney injury.

Pharmaceutical preparations for oral use can be obtained by combining acompound of the present disclosure with a solid excipient, optionallygrinding a resulting mixture, and processing the mixture of granules,after adding suitable auxiliaries, if desired, to obtain tablets ordragee cores. Suitable excipients are, in particular, fillers such assugars, including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents can beadded, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acidor a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of a suitable material, such as gelatin, as well as soft,sealed capsules made of a suitable material, for example, gelatin, and aplasticizer, such as glycerol or sorbitol. The push-fit capsules cancontain the active ingredients in admixture with filler such as lactose,binders such as starches, and/or lubricants such as talc or magnesiumstearate and, optionally, stabilizers. In soft capsules, the activecompounds can be dissolved or suspended in suitable liquids, such asfatty oils, liquid paraffin, or liquid polyethylene glycols. Inaddition, stabilizers can be added. All formulations for oraladministration should be in dosages suitable for such administration.

It will be understood that, certain compounds of the disclosure may beobtained as different stereoisomers (e.g., diastereomers andenantiomers) or as isotopes and that the disclosure includes allisomeric forms, racemic mixtures and isotopes of the disclosed compoundsand a method of treating a subject with both pure isomers and mixturesthereof, including racemic mixtures, as well as isotopes. Stereoisomerscan be separated and isolated using any suitable method, such aschromatography.

F. Delayed Release

NHE proteins show considerable diversity in their patterns of tissueexpression, membrane localization and functional roles. (See, e.g., Thesodium-hydrogen exchanger—From molecule To Is Role In Disease, Karmazyn,M., Avkiran, M., and Fliegel, L., eds., Kluwer Academics (2003).)

In mammals, nine distinct NHE genes (NHE-1 through -9) have beendescribed. Of these nine, five (NHE-1 through -5) are principally activeat the plasma membrane, whereas NHE-6, -7 and -9 reside predominantlywithin intracellular compartments.

NHE-1 is ubiquitously expressed and is chiefly responsible forrestoration of steady state intracellular pH following cytosolicacidification and for maintenance of cell volume. Recent findings showthat NHE-1 is crucial for organ function and survival (e.g., NHE-1-nullmice exhibit locomotor abnormalities, epileptic-like seizures andconsiderable mortality before weaning).

In contrast with NHE-1 expressed at the basolateral side of the nephronsand gut epithelial cells, NHE-2 through -4 are predominantly expressedon the apical side of epithelia of the kidney and the gastrointestinaltract. Several lines of evidence show that NHE-3 is the majorcontributor of renal bulk Na+ and fluid re-absorption by the proximaltubule. The associated secretion of H+ by NHE-3 into the lumen of renaltubules is also essential for about ⅔ of renal HCO3⁻ re-absorption.Complete disruption of NHE-3 function in mice causes a sharp reductionin HCO3⁻, Na⁺ and fluid re-absorption in the kidney, which isconsistently associated with hypovolemia and acidosis.

In one embodiment, the compounds of the disclosure are intended totarget the apical NHE antiporters (e.g. NHE-3, NHE-2 and NHE-8) withoutsubstantial permeability across the layer of gut epithelial cells,and/or without substantial activity towards NHEs that do not residepredominantly in the GI tract. This invention provides a method toselectively inhibit GI apical NHE antiporters and provide the desiredeffect of salt and fluid absorption inhibition to correct abnormal fluidhomeostasis leading to constipations states. Because of their absence ofsystemic exposure, said compounds do not interfere with other keyphysiological roles of NHEs highlighted above. For instance, thecompounds of the disclosure are expected to treat constipation inpatients in need thereof, without eliciting undesired systemic effects,such as for example salt wasting or bicarbonate loss leading tohyponatriemia and acidosis among other disorders.

In another embodiment, the compounds of the disclosure are delivered tothe small bowel with little or no interaction with the upper GI such asthe gastric compartment and the duodenum. The applicant found that anearly release of the compounds in the stomach or the duodenum can havean untoward effect on gastric secretion or bicarbonate secretion (alsoreferred to as “bicarbonate dump”). In this embodiment the compounds aredesigned so as to be released in an active form past the duodenum. Thiscan be accomplished by either a prodrug approach or by specific drugdelivery systems.

As used herein, “prodrug” is to be understood to refer to a modifiedform of the compounds detailed herein that is inactive (or significantlyless active) in the upper GI, but once administered is metabolised invivo into an active metabolite after getting past, for example, theduodenum. Thus, in a prodrug approach, the activity of theNHE-inhibiting compound can be masked with a transient protecting groupthat is liberated after compound passage through the desired gastriccompartment. For example, acylation or alkylation of the essentialguanidinyl functionality of the NHE-inhibiting compound would render itbiochemically inactive; however, cleavage of these functional groups byintestinal amidases, esterases, phosphatases, and the like, as wellenzymes present in the colonic flora, would liberate the active parentcompound. Prodrugs can be designed to exploit the relative expressionand localization of such phase I metabolic enzymes by carefullyoptimizing the structure of the prodrug for recognition by specificenzymes. As an example, the anti-inflammatory agent sulfasalazine isconverted to 5-aminosalicylate in the colon by reduction of the diazobond by intestinal bacteria.

In a drug delivery approach the NHE-inhibiting compounds of thedisclosure are formulated in certain pharmaceutical compositions fororal administration that release the active in the targeted areas of theGI, i.e., jejunum, ileum or colon, the distal ileum and colon, or thecolon.

Methods known from the skilled-in-the-art are applicable. (See, e.g.,Kumar, P. and Mishra, B., Colon Targeted Drug Delivery Systems—AnOverview, Curr. Drug Deliv., 2008, 5 (3), 186-198; Jain, S. K. and Jain,A., Target-specific Drug Release to the Colon., Expert Opin. DrugDeliv., 2008, 5 (5), 483-498; Yang, L., Biorelevant Dissolution Testingof Colon-Specific Delivery Systems Activated by Colonic Microflora, J.Control Release, 2008, 125 (2), 77-86; Siepmann, F.; Siepmann, J.;Walther, M.; MacRae, R. J.; and Bodmeier, R., Polymer Blends forControlled Release Coatings, J. Control Release 2008, 125 (1), 1-15;Patel, M.; Shah, T.; and Amin, A., Therapeutic Opportunities inColon-Specific Drug-Delivery Systems, Crit. Rev. Ther. Drug CarrierSyst., 2007, 24 (2), 147-202; Jain, A.; Gupta, Y.; Jain, S. K.,Perspectives of Biodegradable Natural Polysaccharides for Site-specificDrug Delivery to the Colon., J. Pharm. Sci., 2007, 10 (1), 86-128; Vanden, M. G., Colon Drug Delivery, Expert Opin. Drug Deliv., 2006, 3 (1),111-125; Basit, A. W., Advances in Colonic Drug Delivery, Drugs 2005, 65(14), 1991-2007; Chourasia, M. K.; Jain, S. K., Polysaccharides forColon-Targeted Drug Delivery, Drug Deliv. 2004, 11 (2), 129-148;Shareef, M. A.; Khar, R. K.; Ahuja, A.; Ahmad, F. J.; and Raghava, S.,Colonic Drug Delivery: An Updated Review, AAPS Pharm. Sci. 2003, 5 (2),E17; Chourasia, M. K.; Jain, S. K., Pharmaceutical Approaches to ColonTargeted Drug Delivery Systems, J. Pharm. Sci. 2003, 6 (1), 33-66; and,Sinha, V. R.; Kumria, R., Colonic Drug Delivery: Prodrug Approach,Pharm. Res. 2001, 18 (5), 557-564. Typically, the active pharmaceuticalingredient (API) is contained in a tablet/capsule designed to releasesaid API as a function of the environment (e.g., pH, enzymatic activity,temperature, etc.), or as a function of time. One example of thisapproach is Eudracol™ (Pharma Polymers Business Line of Degussa'sSpecialty Acrylics Business Unit), where the API-containing core tabletis layered with various polymeric coatings with specific dissolutionprofiles. The first layer ensures that the tablet passes through thestomach intact so it can continue through the small intestine. Thechange from an acidic environment in the stomach to an alkalineenvironment in the small intestine initiates the release of theprotective outer layer. As it travels through the colon, the next layeris made permeable by the alkalinity and intestinal fluid. This allowsfluid to penetrate to the interior layer and release the activeingredient, which diffuses from the core to the outside, where it can beabsorbed by the intestinal wall. Other methods are contemplated withoutdeparting from the scope of the present disclosure.

In another example, the pharmaceutical compositions of the invention canbe used with drug carriers including pectin and galactomannan,polysaccharides that are both degradable by colonic bacterial enzymes.(See, e.g., U.S. Pat. No. 6,413,494, the entire contents of which areincorporated herein by reference for all relevant and consistentpurposes.) While pectin or galactomannan, if used alone as a drugcarrier, are easily dissolved in simulated gastric fluid and simulatedintestinal fluid, a mixture of these two polysaccharides prepared at apH of about 7 or above produces a strong, elastic, and insoluble gelthat is not dissolved or disintegrated in the simulated gastric andintestinal fluids, thus protecting drugs coated with the mixture frombeing released in the upper GI tract. When the mixture of pectin andgalactomannan arrives in the colon, it is rapidly degraded by thesynergic action of colonic bacterial enzymes. In yet another aspect, thecompositions of the invention may be used with the pharmaceutical matrixof a complex of gelatin and an anionic polysaccharide (e.g., pectinate,pectate, alginate, chondroitin sulfate, polygalacturonic acid,tragacanth gum, arabic gum, and a mixture thereof), which is degradableby colonic enzymes (U.S. Pat. No. 6,319,518).

In yet other embodiments, fluid-absorbing polymers that are administeredin accordance with treatment methods of the present disclosure areformulated to provide acceptable/pleasant organoleptic properties suchas mouthfeel, taste, and/or to avoid premature swelling/gelation in themouth and in the esophagus and provoke choking or obstruction. Theformulation may be designed in such a way so as to ensure the fullhydration and swelling of the FAP in the GI tract and avoid theformation of lumps. The oral dosages for the FAP may take various formsincluding, for example, powder, granulates, tablets, wafer, cookie andthe like, or are delivered to the small bowel with little or nointeraction with the upper GI such as the gastric compartment and theduodenum.

The above-described approaches or methods are only some of the manymethods reported to selectively deliver an active in the lower part ofthe intestine, and therefore should not be viewed to restrain or limitthe scope of the disclosure.

IV. Preparation of Compounds

The following Reaction Schemes I-IV illustrate methods for makingcompounds of this invention, i.e., compounds of Formula (I). It isunderstood that one skilled in the art may be able to make thesecompounds by similar methods or by combining other methods known to oneskilled in the art. It is also understood that one skilled in the artwould be able to make, in a similar manner as described below, othercompounds of Formula (I) not specifically illustrated below by using theappropriate starting components and modifying the parameters of thesynthesis as needed. The compounds described herein may be made fromcommercially available starting materials or synthesized using knownorganic, inorganic, and/or enzymatic processes. In general, startingcomponents may be obtained from sources such as Sigma Aldrich, LancasterSynthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA,etc, or synthesized according to sources known to those skilled in theart (see, for example, Advanced Organic Chemistry: Reactions,Mechanisms, and Structure, 5th edition (Wiley, December 2000)) orprepared as described in this invention. The general synthetic schemesof precursors, intermediates, and final products shown below are mereillustrations of methods of preparations. The various radicals (e.g.,R¹, R², R¹, R⁴, etc. . . . ) affixed on each generic or sub-genericformula in the schemes below will be understood to represent thecorresponding positional radicals in the compounds of general Formula Iand I′ described above. In other words, in the schemes below only theposition of the radical in the structure will matter in theinterpretation of the synthetic scheme rather than its labelling. Forexample, radicals R¹, R², and R³ can be used interchangeably from onescheme to another without necessarily having the same meaning. Onlytheir position in the generic structure I and I′ will determine theiractual substituents for the synthesis.

Referring to General Reaction Scheme I, an appropriate hydrocinnamicacid A, indanone B, or indene C can be obtained commercially orsynthesized according to methods known in the art and converted to theenantiopure epoxide D via Jacobsen epoxidation conditions. The chiralcompounds obtained (either enantiomer can be used) are then reacted withan amine HNR2R³ (where R² and R³ are as previously defined) to providethe aminoindanol E. Further reaction with phenol F is facilitated byeither formation of the mesylate or other activated intermediate of E orthrough activation using triphenylphosphine and an azodicarboxylate suchas diisopropylazodicarboxylate, diethylaiodicarboxylate,di-tert-butylazodicarboxylate, or the like, providing the rearrangedaminoindanol G. Oxidation and chlorination are achieved through use ofchlorinating reagents such as N-chlorosuccinimide, providing thesulfonyl chloride H. There exist multiple methods of producing thehomodimers compounds (1), including reaction of H with amine dimers J.

Compounds of Formula (1) may also be prepared according to GeneralReaction Scheme 11. Aminoindanols E as obtained previously are reactedwith phenols K (available commercially or synthetically via standardprocedures, where X′=bromo or iodo) using conditions described inGeneral Reaction Scheme I furnishing ether product L. Conversion of thehalide to the thioether G is accomplished through palladium-mediatedcoupling with benzylmercaptan. Further elaboration to the compounds ofstructure (I) is as described in General Reaction Scheme I.

Compounds of Formula (I) are also prepared according to General ReactionScheme III. Beginning with the sulfonyl chloride H, the productsulfonamides N are formed from reaction with an amine M where Y (withprotecting group “PG”, in the case where Y is a primary or secondaryamine) is a protected or masked amine functionality or other functionalhandle. Subsequent removal of the protecting group provides thesulfonamide monomer O followed by dimerization with a bifunctional “X”moiety P generates the compounds of structure (I).

Compounds of Formula (I) can also be prepared according to the GeneralReaction Scheme IV. Phenols F are protected to yield thioethers Q whichare then oxidized to the sulfonyl chloride R using reagents such asN-chlorosuccinimide in acetic acid. Subsequently these sulfonylchlorides R can be coupled with amines M to yield the differentiallyprotected derivatives S. Deprotection to yield phenol T which is thenreacted with E which is activated by either formation of the mesylate orother activated intermediate of E or through using triphenylphosphineand an azodicarboxylate such as diisopropylazodicarboxylate,diethylazodicarboxylate, di-tert-butylazodicarboxylate, or the like,providing the rearranged aminoindanol N. The intermediate is deprotectedto yield the monomer O followed by dimer formation with a core P withleaving groups to yield the compounds of structure (I).

Similar to General Reaction Scheme IV, the compounds of Formula (I) canbe prepared through reaction with a fully dimerized phenolic couplingpartner. Reaction of the dimeric amines J with sulfonyl chlorides R canprovide the dimer U under standard conditions with mild bases such aspyridine or trimethylamine. Removal of the protecting groups gives thephenol V. Intermediate of E is activated by either formation of themesylate or using triphenylphosphine and an azodicarboxylate such asdiisopropylazodicarboxylate, diethylazodicarboxylate,di-tert-butylazodicarboxylate, or the like, then reacting with phenol Vproviding the rearranged final compounds of structure (1).

With regard to General Reaction Schemes I-IV, typical carboxylateactivation reagents include DCC, EDCl, HATU, oxalyl chloride, thionylchloride and the like. Typical bases include TEA, DIEA, pyridine, K₂CO₃,NaH and the like. Typical acylation catalysts include HOBt, HOAt,4-dimethylaminopyridine and the like. Typical catalysts forhydrogenation include palladium on carbon, rhodium on carbon, platinumon carbon, raney nickel and the like.

One skilled in the art will recognize that variations to the order ofthe steps and reagents discussed in reference to the Reaction Schemesare possible. Methodologies for preparation of compounds of Formula (I)are described in more detail in the following non-limiting exemplaryschemes.

It will also be appreciated by those skilled in the art that in theprocess described herein the functional groups of intermediate compoundsmay need to be protected by suitable protecting groups. Such functionalgroups include hydroxy, amino, mercapto and carboxylic acid. Suitableprotecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl(for example, t-butyldimethylsilyl, f-butyldiphenylsilyl ortrimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitableprotecting groups for amino, amidino and guanidino includei-butoxycarbonyl, benzyloxycarbonyl, trifluoroacetyl and the like.Suitable protecting groups for carboxylic acid include alkyl, aryl orarylalkyl esters. Protecting groups may be added or removed inaccordance with standard techniques, which are known to one skilled inthe art and as described herein. The use of protecting groups isdescribed in detail in Green, T. W. and P. G. M. Wutz, Protective Groupsin Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill in the artwould appreciate, the protecting group may also be a polymer resin suchas a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this invention may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds of theinvention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds of thisinvention are included within the scope of the invention.

The following non-limiting examples are provided to further illustratethe present disclosure.

EXAMPLES I General Scheme for Linker Synthesis

Step A: To a 250-mL round-bottom flask was added the desiredsubstituted-bromophenol (1 equiv), acetone (0.45 M), potassium carbonate(5 equiv), and benzyl bromide (2.5 equiv). The resulting solution wasstirred for 4 h at room temperature. The resulting solution was dilutedwith 30 mL of H₂O. The resulting mixture was concentrated under vacuumand extracted with of ethyl acetate. The organic layers were combinedand washed with 3×H₂O and 1× brine. The mixture was dried over anhydroussodium sulfate, filtered, and the resulting mixture concentrated undervacuum. The residue was applied onto a silica gel column with petroleumether providing the desired benzylethers INT-L1.

Step B: To a round-bottom flask purged and maintained with an inertatmosphere of nitrogen was added benzylether INT-L1 (1 equiv),1,4-dioxane (0.16 M), N,N-diisopropylethylamine (2 equiv),benzylmercaptan (2 equiv), Pd₂(dba)₃.CHCl₃ (0.05 equiv), and Xantphos(0.10 equiv). The resulting solution was stirred overnight at 100° C.The resulting slurry was concentrated under vacuum and diluted with ofH₂O. The resulting solution was extracted with of ethyl acetate and theorganic layers combined and washed with 3×H₂O and 1× brine. The mixturewas dried over anhydrous sodium sulfate, filtered, and the resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with petroleum ether providing the desired thioethersINT-L2.

Step C: To a round-bottom flask was added thioether INT-L2 (1 equiv),acetic acid (0.25 M), and water (3 equiv). This was followed by theaddition of N-chlorosuccinimide (NCS, 5 equiv) in several batches at 0°C. The resulting solution was stirred for 1 h at room temperature. Theresulting slurry was concentrated under vacuum and diluted with H₂O. Theresulting solution was extracted with of ethyl acetate and the organiclayers combined and washed with 3×H₂O and 1× brine. The mixture wasdried over anhydrous sodium sulfate, filtered, and concentrated undervacuum. The residue was applied onto a silica gel column with petroleumether providing the sulfonyl chloride INT-L3.

Step D: To a round-bottom flask was added sulfonyl chloride INT-L3 (1equiv), CH₂Cl₂ (0.2 M), triethylamine (5 equiv), andN-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-2,2,2-trifluoroacetamide (INT-L4, 2equiv). The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum anddiluted with of H₂O. The resulting slurry was extracted with CH₂C₁₂ andthe organic layers combined and washed with 3×H₂O and 1× brine. Themixture was dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with CH₂Cl₂/methanol (30:1) providing the sulfonamide INT-L5.

Step E: To a round-bottom flask purged and maintained with an inertatmosphere of H₂, was added sulfonamide INT-L5 (1 equiv), methanol (0.1M), and palladium on carbon (˜10-20%). The resulting slurry was stirredfor 1 h at room temperature. The solids were filtered out and theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:1)providing the desired phenol INT-L6.

The following intermediates were made by applying the above proceduresto the appropriate phenol:

General Scheme for Indane Epoxide Synthesis

Step A: To a round-bottom flask purged and maintained with an inertatmosphere of nitrogen was added the desired R⁴-substitutedbromide/iodide (1 equiv), CH₃CN (0.25 M), tert-butyl prop-2-enoate(equiv), diisopropylethylamine (3 equiv), P(o-tol)₃ (0.20 equiv), andPd(OAc)₂ (0.10 equiv). The resulting solution was stirred overnight at95° C. The solids were removed by filtration and the filtrate wasconcentrated under vacuum. The resulting slurry was diluted with waterand extracted with 3×CH₂Cl₂. The organic layers were combined and driedover anhydrous sodium sulfate, filtered, and concentrated. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(1:500) providing the cinnamate INT-I1.

Step B: To a round-bottom flask was cinnamate INT-I1 (1 equiv), ethylacetate (0.1 M), and Raney Ni. The flask was purged and filled withH_(2(g)), cycling three times, leaving a positive H₂ atmosphere. Theresulting solution was stirred for 2 h at room temperature. The solidswere filtered out and the resulting mixture was concentrated undervacuum providing the hydrocinnamate INT-I2.

Step C: To a round-bottom flask was added hydrocinnamate INT-I2 (1equiv) and 2:1 CH₂Cl₂:TFA (0.4 M). The resulting slurry was stirred for1 h at room temperature. The resulting mixture was concentrated undervacuum and the residue was applied onto a silica gel column with ethylacetate/petroleum ether (0-10%). The collected fractions were combinedand concentrated under vacuum providing the hydrocinnamic acid INT-I3.

Step D: To a 3-necked round-bottom flask was added hydrocinnamic acidINT-I3 (1 equiv) and CH₂Cl₂ (0.4 M). The reaction slurry was cooled to0° C. and treated with (COCl)₂ (2 equiv) dropwise. The resultingsolution was stirred for 2 h at room temperature. The resulting solutionwas concentrated under vacuum. To a 3-necked round-bottom flask wasadded AlICl₃ (2 equiv) and CH₂Cl₂ (0.4 M). The product of the first stepdissolved in CH₂Cl₂ and added dropwise to this AICI3 slurry. Theresulting solution was stirred for 2 h at 40° C. in an oil bath. Thereaction was then quenched by the addition of 2N HCl_((aq)). Theresulting solution was extracted with 3×CH₂Cl₂ and the organic layerscombined and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (0-1:10). Thecollected fractions were combined and concentrated under vacuumproviding the indanone INT-I4.

Step E: To a round-bottom flask was indanone INT-I4 (1 equiv), methanol(0.7 M), and NaBH₄ (2 equiv). The resulting solution was stirred for 1 hat room temperature. The reaction was then quenched by the addition of20 mL of water and extracted with 3×CH₂Cl₂. The organic layers werecombined and washed with 3× brine. The organic layer was dried overanhydrous sodium sulfate, filtered, and concentrated under vacuumproviding indanol INT-I5.

Step F: To a round-bottom flask was added indanol INT-I5 (1 equiv),methanol (0.5 M), and HCl (half volume of methanol). The resultingsolution was stirred for 1 h at room temperature. The resulting mixturewas quenched with methanol and concentrated under vacuum. The resultingslurry was extracted with 3×n-hexane and the organic layers combined.The residue was applied onto a silica gel column with n-hexane providingindene INT-I6.

Step G: To a 3-necked round-bottom flask was added indene INT-I6 (1equiv), CH₂Cl₂ (0.08M, dried over magnesium sulfate), pyridine N-oxide(5 equiv in CH₂Cl₂ solution dried over magnesium sulfate), and(S,S)-Jacobsen's catalyst (0.05 equiv). The resulting solution wasstirred for 10 min at 0° C. followed by the addition of m-CPBA (2 equiv)in portions at 0° C. The resulting slurry was stirred for an additional1 h at 0° C. The reaction was then quenched by the addition of sodiumhydroxide (3 M_((aq)), approx. 13 equiv). The resulting slurry waswashed with 1×H₂O and 1× brine. The mixture was dried over anhydroussodium sulfate, filtered, and concentrated. The residue was applied ontoa silica gel column with ethyl acetate/petroleum ether (1:30-1:15)providing the epoxide INT-I7.

The following intermediates were made by applying the above proceduresto the appropriate starting aryl compounds (starting materials areavailable commercially at different stages of this sequence):

General Scheme for Aminoindanol Synthesis

To a round-bottom flask was added epoxide INT-I7 (1 equiv), the desiredamine R²R³NH (2 equiv), and CH₃CN (0.16 M). The resulting solution washeated to reflux for 16 h. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:3-1:2) providing the aminoindanol INT-I8.

The following intermediates are made by applying the above procedures tothe appropriate starting epoxides and amines:

Subsequent Substitutions of Aminoindanols

To a round-bottom flask purged and maintained with an inert atmosphereof nitrogen was added INT-I8 bromide (1 equiv), CH₃B(OH)₂ (1.5 equiv),PPh₃ (0.10 equiv), K₃PO₄ (4 equiv), tetrahydrofuran (0.3 M), andPd(OAc)₂ (0.05 equiv). The resulting solution was stirred for 2 h at 80°C. The reaction was then quenched by the addition of H₂O and extractedwith 3× ethyl acetate. The organic layers were combined, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was applied onto a silica gel column with CH₂C₁₂/methanol(10:1). The collected fractions were combined and concentrated undervacuum providing the 4-methyl substituted aminoindanols INT-I9.

The following intermediates are made by applying the above procedures tothe appropriate starting 4-bromo aminoindanols:

To a round-bottom flask purged and maintained with an inert atmosphereof nitrogen was added 4-bromoaminoindanol INT-I8 (1 equiv), Zn(CN)₂(0.60 equiv), Pd(PPh₃)₄ (0.10 equiv), and NMP (DMF on the scheme) (0.4M). The resulting slurry was stirred overnight at 95° C. The reactionslurry was cooled and extracted with 3× ethyl acetate. The combinedorganic layers were washed with 3× brine, dried over anhydrous sodiumsulfate, filtered, and concentrated. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:1) providing the4-cyano substituted aminoindanols INT-I10.

The following intermediates are made by applying the above procedures tothe appropriate starting 4-bromo aminoindanols:

Step A: To a round-bottom flask purged and maintained with an inertatmosphere of nitrogen was added 4-bromoaminoindanol INT-I8B (orINT-I8H) (1 equiv), CH₂Cl₂ (0.25 M), and imidazole (3 equiv). This wasfollowed by the addition of TBSCl (1.5 equiv) in several batches at 0°C. The resulting slurry was stirred overnight at room temperature. Thereaction was quenched by the addition of H₂O and extracted with 3× ethylacetate. The organic layers were combined, washed with 1× brine, driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1/10) providing the TBS-protectedintermediates.

Step B: To a round-bottom flask purged and maintained with an inertatmosphere of nitrogen was added the TBS-protected aminoindanol (1equiv), Cs₂CO₃ (3 equiv), and methanol (8 equiv). A solution of 3rdGeneration BrettPhos precatalyst (0.05 equiv) in dioxane (0.5 M) wasadded. The resulting slurry was stirred for 2 h at 60° C. in an oilbath. The reaction was quenched by the addition of H₂O and extractedwith 3× ethyl acetate. The organic layers were combined, washed with 1×brine, dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1/5) providing the 4-methoxy substitutedaminoindanol TBS-ethers.

Step C: To a round-bottom flask purged and maintained with an inertatmosphere of nitrogen was added 4-methoxy substituted aminoindanolTBS-ether (1 equiv) and tetrahydrofuran (0.5 M). TBAF (1.5 equiv, 1M THFsolution) was added and the resulting solution stirred for 1 h at roomtemperature. The reaction slurry was diluted with 1:1 EtOAc:Et₂O andwashed with 3×H₂O. The mixture was dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1/1) providing4-methoxy substituted aminoindanols INT-I11A and B.

General Scheme for Monomer Synthesis:

Step A: To a round-bottom flask was added aminoindanol INT-I8 (1 equiv)and tetrahydrofuran (0.2 M), followed by the addition of phenol linkerINT-L6 (1.1 equiv) and heating to 40° C. To this slurry was added PPh₃(2 equiv) and DIAD (1.5 equiv). The resulting solution was stirred for1.5 h at 40° C. The resulting mixture was concentrated under vacuum anddiluted with CH₂Cl₂. The residue was applied onto a silica gel columnwith ethyl acetate/petroleum ether (1:1) providing indane monomerINT-M1.

Step B: To a round-bottom flask was added indane monomer INT-M1 (1equiv), methanol (0.1 M), and sodium hydroxide (3 M_((aq)), 3 equiv).The resulting solution was stirred for 1.5 h at 60° C. The resultingmixture was concentrated under vacuum and diluted with CH₂Cl₂. Theresidue was applied onto a silica gel column with ethyl acetate (100%)providing indane amine monomer INT-M2.

The following intermediates are made by applying the above procedures tothe appropriate starting aminoindanols INT-I8 and linkers INT-L6:

General Scheme for Dimer Formation (Non-Protected Analogs):

To a round-bottom flask was added INT-M2 (1 equiv),N,N-dimethylformamide (DMF, 0.12 M), and 1,4-diisocyanatobutane (0.40equiv). The resulting solution was stirred for 2 h at 60° C. Theresulting mixture was concentrated under vacuum and diluted with CH₂Cl₂.The residue was applied onto a silica gel column withchloroform/methanol (10:1) providing the desired dimer Product 1. Finalproducts were purified by Preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm;mobile phase, water (0.05% TFA) and CH₃CN (10.0% CH₃CN up to 70.0% in 8min); Detector, UV 254 nm. The final products were generally isolated asthe TFA salts or exchanged to the hydrochloride salts.

General Scheme for Deprotection of Dimers:

To a round-bottom flask was added Boc-protected dimers (1 equiv) and 3:1CH₂Cl₂:TFA (˜0.05 M). The resulting solution was stirred for 2 h at roomtemperature. The resulting mixture was concentrated under vacuum. Thecrude product was purified by Preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm;mobile phase, water (0.05% TFA) and CH₃CN (10.0% CH₃CN up to 70.0% in 8min); Detector, UV 254 nm. The final dimer Products 1 were generallyisolated as the TFA salts or exchanged to the hydrochloride salts.

General Scheme for Linker Synthesis

Step A: To a 250-mL round-bottom flask was added the desiredsubstituted-bromophenol (1 equiv), acetone (0.45 M), potassium carbonate(5 equiv), and benzyl bromide (2.5 equiv). The resulting solution wasstirred for 4 h at room temperature. The resulting solution was dilutedwith 30 mL of H₂O. The resulting mixture was concentrated under vacuumand extracted with of ethyl acetate. The organic layers were combinedand washed with 3×H₂O and 1× brine. The mixture was dried over anhydroussodium sulfate, filtered, and the resulting mixture concentrated undervacuum. The residue was applied onto a silica gel column with petroleumether providing the desired benzylethers INT-L1.

Step B: To a round-bottom flask purged and maintained with an inertatmosphere of nitrogen was added benzylether INT-L1 (1 equiv),1,4-dioxane (0.16 M), N,N-diisopropylethylamine (2 equiv),benzylmercaptan (2 equiv), Pd₂(dba)₃-CHCl₃ (0.05 equiv), and Xantphos(0.10 equiv). The resulting solution was stirred overnight at 100° C.The resulting slurry was concentrated under vacuum and diluted with ofH₂O. The resulting solution was extracted with of ethyl acetate and theorganic layers combined and washed with 3×H₂O and 1× brine. The mixturewas dried over anhydrous sodium sulfate, filtered, and the resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with petroleum ether providing the desired thioethersINT-L2.

Step C: To a round-bottom flask was added thioether INT-L2 (1 equiv),acetic acid (0.25 M), and water (3 equiv). This was followed by theaddition of N-chlorosuccinimide (NCS, 5 equiv) in several batches at 0°C. The resulting solution was stirred for 1 h at room temperature. Theresulting slurry was concentrated under vacuum and diluted with H₂O. Theresulting solution was extracted with of ethyl acetate and the organiclayers combined and washed with 3×H₂O and 1× brine. The mixture wasdried over anhydrous sodium sulfate, filtered, and concentrated undervacuum. The residue was applied onto a silica gel column with petroleumether providing the sulfonyl chloride INT-L3.

Step D: To a round-bottom flask was added sulfonyl chloride INT-L3 (1equiv), CH₂Cl₂ (0.2 M), triethylamine (5 equiv), andN-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-2,2,2-trifluoroacetamide (INT-L4, 2equiv). The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum anddiluted with of H₂O. The resulting slurry was extracted with CH₂Cl₂ andthe organic layers combined and washed with 3×H₂O and 1× brine. Themixture was dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with CH₂₂C/methanol (30:1) providing the sulfonamide INT-L5.

Step E: To a round-bottom flask purged and maintained with an inertatmosphere of 112, was added sulfonamide INT-L5 (1 equiv), methanol (0.1M), and palladium on carbon (˜10-20%). The resulting slurry was stirredfor 1 h at room temperature. The solids were filtered out and theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1: I)providing the desired phenol INT-L6.

The following intermediates were made by applying the above proceduresto the appropriate phenol:

General Scheme for Indane Epoxide Synthesis

Step A: To a round-bottom flask purged and maintained with an inertatmosphere of nitrogen was added the desired R⁴-substitutedbromide/iodide (1 equiv), CH₃CN (0.25 M), tert-butyl prop-2-enoate(equiv), diisopropylethylamine (3 equiv), P(o-tol)₃ (0.20 equiv), andPd(OAc)₂ (0.10 equiv). The resulting solution was stirred overnight at95° C. The solids were removed by filtration and the filtrate wasconcentrated under vacuum. The resulting slurry was diluted with waterand extracted with 3×CH₂Cl₂. The organic layers were combined and driedover anhydrous sodium sulfate, filtered, and concentrated. The residuewas applied onto a silica gel column with ethyl acetate/petroleum ether(1:500) providing the cinnamate INT-I1.

Step B: To a round-bottom flask was cinnamate INT-I1 (1 equiv), ethylacetate (0.1 M), and Raney Ni. The flask was purged and filled withH_(2(g)), cycling three times, leaving a positive H₂ atmosphere. Theresulting solution was stirred for 2 h at room temperature. The solidswere filtered out and the resulting mixture was concentrated undervacuum providing the hydrocinnamate INT-I2.

Step C: To a round-bottom flask was added hydrocinnamate INT-I2 (1equiv) and 2:1 CH₂Cl₂:TFA (0.4 M). The resulting slurry was stirred for1 h at room temperature. The resulting mixture was concentrated undervacuum and the residue was applied onto a silica gel column with ethylacetate/petroleum ether (0-10%). The collected fractions were combinedand concentrated under vacuum providing the hydrocinnamic acid INT-I3.

Step D: To a 3-necked round-bottom flask was added hydrocinnamic acidINT-I3 (I equiv) and CH₂Cl₂ (0.4 M). The reaction slurry was cooled to0° C. and treated with (COCI)₂ (2 equiv) dropwise. The resultingsolution was stirred for 2 h at room temperature. The resulting solutionwas concentrated under vacuum. To a 3-necked round-bottom flask wasadded AlCl₃ (2 equiv) and CH₂Ch (0.4 M). The product of the first stepdissolved in CH₂Cl₂ and added dropwise to this AlCl₃ slurry. Theresulting solution was stirred for 2 h at 40° C. in an oil bath. Thereaction was then quenched by the addition of 2N HCl_((aq)). Theresulting solution was extracted with 3×CH₂Cl₂ and the organic layerscombined and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (0-1:10). Thecollected fractions were combined and concentrated under vacuumproviding the indanone INT-I4.

Step E: To a round-bottom flask was indanone INT-I4 (1 equiv), methanol(0.7 M), and NaBH₄ (2 equiv). The resulting solution was stirred for 1 hat room temperature. The reaction was then quenched by the addition of20 mL, of water and extracted with 3×CH₂Cl₂. The organic layers werecombined and washed with 3× brine. The organic layer was dried overanhydrous sodium sulfate, filtered, and concentrated under vacuumproviding indanol INT-I5.

Step F: To a round-bottom flask was added indanol INT-I5 (1 equiv),methanol (0.5 M), and HCl (half volume of methanol). The resultingsolution was stirred for 1 h at room temperature. The resulting mixturewas quenched with methanol and concentrated under vacuum. The resultingslurry was extracted with 3×n-hexane and the organic layers combined.The residue was applied onto a silica gel column with n-hexane providingindene INT-I6.

Step G: To a 3-necked round-bottom flask was added indene INT-I6 (1equiv), CH₂Cl₂ (0.08M, dried over magnesium sulfate), pyridine N-oxide(5 equiv in CH₂Cl₂ solution dried over magnesium sulfate), and(S,S)-Jacobsen's catalyst (0.05 equiv). The resulting solution wasstirred for 10 min at 0° C. followed by the addition of m-CPBA (2 equiv)in portions at 0° C. The resulting slurry was stirred for an additional1 h at 0° C. The reaction was then quenched by the addition of sodiumhydroxide (3 M_((aq)), approx. 13 equiv). The resulting slurry waswashed with 1×H₂O and 1× brine. The mixture was dried over anhydroussodium sulfate, filtered, and concentrated. The residue was applied ontoa silica gel column with ethyl acetate/petroleum ether (1:30-1:15)providing the epoxide INT-I7.

The following intermediates were made by applying the above proceduresto the appropriate starting aryl compounds (starting materials areavailable commercially at different stages of this sequence):

General Scheme for Aminoindanol Synthesis

To a round-bottom flask was added epoxide INT-I7 (1 equiv), the desiredamine R²R³NH (2 equiv), and CH₃CN (0.16 M). The resulting solution washeated to reflux for 16 h. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:3-1:2) providing the aminoindanol INT-I8.

The following intermediates are made by applying the above procedures tothe appropriate starting epoxides and amines:

Subsequent Substitutions of Aminoindanols

To a round-bottom flask purged and maintained with an inert atmosphereof nitrogen was added INT-I8 bromide (1 equiv), CH₃B(OH)₂ (1.5 equiv),PPh3 (0.10 equiv), K3P04 (4 equiv), tetrahydrofuran (0.3 M), andPd(OAc)₂ (0.05 equiv). The resulting solution was stirred for 2 h at 80°C. The reaction was then quenched by the addition of H₂O and extractedwith 3× ethyl acetate. The organic layers were combined, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was applied onto a silica gel column with CH₂Cl₂/methanol(10:1). The collected fractions were combined and concentrated undervacuum providing the 4-methyl substituted aminoindanols INT-I9.

The following intermediates are made by applying the above procedures tothe appropriate starting 4-bromo aminoindanols:

To a round-bottom flask purged and maintained with an inert atmosphereof nitrogen was added 4-bromoaminoindanol INT-I8 (1 equiv), Zn(CN)₂(0.60 equiv), Pd(PPh₃)₄ (0.10 equiv), and NMP (DMF on the scheme) (0.4M). The resulting slurry was stirred overnight at 95° C. The reactionslurry was cooled and extracted with 3× ethyl acetate. The combinedorganic layers were washed with 3× brine, dried over anhydrous sodiumsulfate, filtered, and concentrated. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:1) providing the4-cyano substituted aminoindanols INT-I10.

The following intermediates are made by applying the above procedures tothe appropriate starting 4-bromo aminoindanols:

Step A: To a round-bottom flask purged and maintained with an inertatmosphere of nitrogen was added 4-bromoaminoindanol INT-I8B (orINT-18H) (1 equiv), CH₂Cl₂ (0.25 M), and imidazole (3 equiv). This wasfollowed by the addition of TBSCl (1.5 equiv) in several batches at 0°C. The resulting slurry was stirred overnight at room temperature. Thereaction was quenched by the addition of H₂O and extracted with 3× ethylacetate. The organic layers were combined, washed with 1× brine, driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1/10) providing the TBS-protectedintermediates.

Step B: To a round-bottom flask purged and maintained with an inertatmosphere of nitrogen was added the TBS-protected aminoindanol (1equiv), Cs₂CO₃ (3 equiv), and methanol (8 equiv). A solution of 3rdGeneration BrettPhos precatalyst (0.05 equiv) in dioxane (0.5 M) wasadded. The resulting slurry was stirred for 2 h at 60° C. in an oilbath. The reaction was quenched by the addition of H₂O and extractedwith 3× ethyl acetate. The organic layers were combined, washed with 1×brine, dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1/5) providing the 4-methoxy substitutedaminoindanol TBS-ethers.

Step C: To a round-bottom flask purged and maintained with an inertatmosphere of nitrogen was added 4-methoxy substituted aminoindanolTBS-ether (1 equiv) and tetrahydrofuran (0.5 M). TBAF (1.5 equiv, 1M THFsolution) was added and the resulting solution stirred for 1 h at roomtemperature. The reaction slurry was diluted with 1:1 EtOAc:Et₂O andwashed with 3×H₂O. The mixture was dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1/1) providing4-methoxy substituted aminoindanols INT-IIIA and B.

General Scheme for Monomer Synthesis:

Step A: To a round-bottom flask was added aminoindanol INT-I8 (1 equiv)and tetrahydrofuran (0.2 M), followed by the addition of phenol linkerINT-L6 (1.1 equiv) and heating to 40° C. To this slurry was added PPh₃(2 equiv) and DIAD (1.5 equiv). The resulting solution was stirred for1.5 h at 40° C. The resulting mixture was concentrated under vacuum anddiluted with CH₂Cl₂. The residue was applied onto a silica gel columnwith ethyl acetate/petroleum ether (1:1) providing indane monomerINT-M1.

Step B: To a round-bottom flask was added indane monomer INT-M1 (1equiv), methanol (0.1 M), and sodium hydroxide (3 M_((aq)), 3 equiv).The resulting solution was stirred for 1.5 h at 60° C. The resultingmixture was concentrated under vacuum and diluted with CH₂Cl₂. Theresidue was applied onto a silica gel column with ethyl acetate (100%)providing indane amine monomer INT-M2.

The following intermediates are made by applying the above procedures tothe appropriate starting amninoindanols INT-I8 and linkers INT-L6:

General Scheme for Dimer Formation (Non-Protected Analogs):

To a round-bottom flask was added INT-M2 (1 equiv),N,N-dimethylformamide (DMF, 0.12 M), and 1,4-diisocyanatobutane (0.40equiv). The resulting solution was stirred for 2 h at 60° C. Theresulting mixture was concentrated under vacuum and diluted with CH₂Cl₂.The residue was applied onto a silica gel column withchloroform/methanol (10:1) providing the desired dimer Product 1. Finalproducts were purified by Preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm;mobile phase, water (0.05% TFA) and CH₃CN (10.0% CH₃CN up to 70.0% in 8min); Detector, UV 254 nm. The final products were generally isolated asthe TFA salts or exchanged to the hydrochloride salts.

General Scheme for Deprotection of Dimers:

To a round-bottom flask was added Boc-protected dimers (1 equiv) and 3:1CH₂CL₂:TFA (˜0.05 M). The resulting solution was stirred for 2 h at roomtemperature. The resulting mixture was concentrated under vacuum. Thecrude product was purified by Preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm;mobile phase, water (0.05% TFA) and CH₃CN (10.0% CH₃CN up to 70.0% in 8min); Detector, UV 254 nm. The final dimer Products 1 were generallyisolated as the TFA salts or exchanged to the hydrochloride salts.

Example 1:1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy)ethoxy)ethyl]carbamoyl]amino)butyl]urea

Prepared according to the General Scheme above from INT-M2A.Purification by preparative HPLC with the following conditions: Column,XBridge Shield RP18 OBD Column, 19*250 mm, 10 um; mobile phase, water(0.05% HCl) and CH₃CN (26.0% CH₃CN up to 47.0% in 8 min); Detector, UV254 nm. This resulted in 695.3 mg (38%) of the title compound as a lightyellow solid. MS (m/z): 1343.4 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ7.74 (s, 2H), 7.82 (d, J=8.4 Hz, 2H), 7.49 (t, J=8.4 Hz, 4H), 7.12 (s,2H), 6.31 (s, 2H), 4.01 (s, 2H), 3.68-3.42 (m, 20H), 3.33-3.29 (m, 6H),3.28-3.00 (m, 12H), 2.85 (s, 4H), 2.26 (s, 6H), 2.01 (s, 4H), 1.82 (s,2H), 1.67 (d, J=9.6 Hz, 2H), 1.50 (s, 2H).

Example 2:3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,1S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea,bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2B by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following conditions: Column, XSelect CSH Preparative C18 OBDColumn, 19* 150 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN (15%CH₃CN up to 45% in 8 min); Detector, UV 254 nm. This resulted in 192.6mg (56%) of the title compound as a white solid. MS (m/z): 1351 [M+H]⁺.¹H NMR (Methanol-d4, 400 MHz) δ 8.50 (s, 2H), 7.76-7.56 (m, 6H), 7.45(d, J=1.7 Hz, 2H), 7.20 (d, J=1.7 Hz, 2H), 6.01 (d, J=5.2 Hz, 2H), 3.71(td, J=7.1, 5.1 Hz, 2H), 3.62-3.46 (m, 16H), 3.31-3.17 (m, 6H), 3.09(dd, J=6.2, 4.3 Hz, 8H), 2.99 (dd, J=16.8, 6.8 Hz, 2H), 2.88 (d, J=11.4Hz, 2H), 2.65 (s, 2H), 2.60-2.48 (m, 4H), 1.97-1.87 (m, 2H), 1.87-1.77(m, 2H), 1.68-1.42 (m, 8H).

Example 3:3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Prepared according to the General Scheme above from INT-M2C by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following conditions: Column, XBridge C18 OBD Preparative Column,19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN (10.0% CH₃CNup to 70.0% in 8 min); Detector, UV 254 nm. This resulted in 42.3 mg(26%) of the title compound as a white solid. MS (m/z): 1273 [M+H]⁺. ¹HNMR (Methanol-d4, 400 MHz) δ 7.91-7.83 (m, 4H), 7.32-7.25 (m, 4H), 7.18(d, J=1.7 Hz, 2H), 7.00 (d, J=1.7 Hz, 2H), 6.00 (s, 2H), 3.68 (s, 2H),3.61-3.46 (m, 16H), 3.38 (s, 1H), 3.27 (d, J==5.4 Hz, 3H), 3.19 (d,J=17.9 Hz, 4H), 3.09 (d, J=5.2 Hz, 8H), 2.93 (s, 4H), 2.78 (s, 2H), 2.63(s, 4H), 2.30 (s, 6H), 1.92 (s, 3H), 1.86 (s, 1H), 1.69 (s, 3H), 1.59(d, J=10.3 Hz, 2H), 1.50-1.42 (m, 4H).

Example 4:3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethy]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2D by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following conditions: Column, XBridge C18 OBD Preparative Column,19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN (25.0% CH₃CNup to 45.0% in 8 min); Detector, UV 254 nm. This resulted in 143.9 mg(71%) of the title compound as a white solid. MS (m/z): ¹H NMR(Methanol-d4, 400 MHz) δ 7.85 (d, J=8.6 Hz, 4H), 7.75 (d, J=1.9 Hz, 2H),7.47 (d, J=1.8 Hz, 2H), 7.29 (d, J=8.7 Hz, 4H), 6.02 (d, J=5.5 Hz, 2H),3.72 (d, J=6.5 Hz, 2H), 3.59-3.42 (m, 16H), 3.41-3.29 (m, 1H), 3.24 (d,J=5.4 Hz, 3H), 3.20-2.99 (m, 11H), 2.89 (d, J=11.5 Hz, 2H), 2.66-2.52(m, 7H), 1.87 (s, 4H), 1.44 (s, 4H).

Example 5:3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1[-4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2E by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following conditions: Column, XBridge C18 OBD Preparative Column,19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN (18.0% CH₃CNup to 32.0% in 8 min); Detector, UV 254 nm. This resulted in 227.2 mg(74%) of the title compound as a white solid. MS (m/z): 135 [M+H]⁺. ¹HNMR (Methanol-d4, 400 MHz) δ 7.88 (d, J=8.3 Hz, 4H), 7.34-7.26 (m, 4H),6.96 (s, 2H), 6.77 (s, 2H), 6.09 (d, J=19.2 Hz, 2H), 3.86 (s, 6H),3.61-3.46 (m, 17H), 3.42 (s, 2H), 3.28 (t, J=5.4 Hz, 4H), 3.13-3.04 (m,8H), 2.72 (s, 6H), 1.96 (s, 4H), 1.74 (s, 2H), 1.61 (s, 2H), 1.50-1.42(m, 4H).

Example 6:1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Prepared according to the General Scheme above from INT-M2F by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following conditions: Column, XBridge C18 OBD Preparative Column,19*250 mm; mobile phase, water (0.05% HCl) and CH₃CN (34% CH₃CN up to54% in 8 min); Detector, UV 254 nm. This resulted in 168.1 mg (51%) ofthe titled compound as a light yellow solid. MS (m/z): 1311.45 M+H]⁺. ¹HNMR (Methanol-d4, 400 MHz) δ 7.85 (d, J=2.4 Hz, 2H), 7.82 (s, 2H), 7.55(d, J=8.8 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 6.91 (s, 2H), 6.77 (d, J=6.4Hz, 2H), 4.54 (d, J=6.8 Hz, 2H), 3.89-3.70 (m, 8H), 3.57-3.49 (m, 17H),3.31-3.23 (m, 10H), 3.18-3.08 (m, 9H), 2.30 (s, 6H), 2.19-2.07 (m, 6H),1.75 (s, 2H), 1.48 (s, 4H).

Example 7:3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Prepared according to the General Scheme above from INT-M2G by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following conditions: Column, XSelect CSH Preparative C18 OBDColumn, 19*150 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN(16.0% CH₃CN up to 40.0% in 8 min); Detector, UV 254 nm. This resultedin 157 mg (52%) of the title compound as a white solid. MS (m/z): 1301[M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) 7.77 (d, J=9.0 Hz, 2H), 7.70 (s,2H), 7.44 (d, J=8.5 Hz, 2H), 7.18 (s, 2H), 6.97 (d, J=6.5 Hz, 2H), 3.28(t, J=5.4 Hz, 6H), 3.08 (dt, J=10.9, 5.5 Hz, 10H), 2.94 (s, 4H), 2.73(s, 5H), 3.61-3.46 (m, 16H), 2.27 (d, J=22.7 Hz, 13H), 1.95 (s, 5H),1.67 (d, =49.5 Hz, 5H), 1.50-1.42 (m, 4H).

Example 8:3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2H by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following conditions: Column, XBridge C18 OBD Preparative Column,19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN (24.0% CH₃CNup to 41.0% in 7 min): Detector, UV 254 nm. This resulted in 30.1 mg(25%) of the title compound as a white solid. MS (m/z): 661.7 [M/2+H]⁺.¹H NMR (Methanol-d4, 400 MHz) δ 7.81-7.68 (m, 6H), 7.50-7.42 (m, 4H),6.08 (d, J=6.6 Hz, 2H), 3.78 (d, J=8.2 Hz, 2H), 3.53 (dtd, J=22.6, 5.4,2.5 Hz, 16H), 3.45-3.33 (m, 6H), 3.27 (d, J=5.5 Hz, 3H), 3.18 (d, J=7.6Hz, 2H), 3.13-3.02 (m, 8H), 2.92 (s, 2H), 2.66 (d, J=27.7 Hz, 6H), 2.25(s, 6H), 1.83 (s, 4H), 1.69-1.55 (m, 4H), 1.46 (p, J=3.2 Hz, 4H).

Example 9:3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1[-4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2J by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following conditions: Column, XBridge C18 OBD Preparative Column,19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN (30.0% CH₃CNup to 38.0% in 12 min); Detector, UV 254 nm. This resulted in 19.5 mg(13%) of the title compound as a white solid. MS (m/z): 1334 [M+H]⁺. ¹HNMR (Methanol-d4, 400 MHz) δ 7.81-7.73 (m, 2H), 7.70 (dd, J=2.4, 1.0 Hz,2H), 7.43 (d, J=8.7 Hz, 2H), 6.94 (d, J=1.6 Hz, 2H), 6.75 (d, J=1.5 Hz,2H), 6.03 (d, J=5.4 Hz, 2H), 3.86 (s, 6H), 3.75-3.67 (m, 2H), 3.61-3.46(m, 15H), 3.38 (dd, J=7.9, 4.4 Hz, 2H), 3.32-3.16 (m, 5H), 3.08 (dt,J=11.0, 5.7 Hz, 8H), 2.98 (d, J=11.5 Hz, 2H), 2.92-2.78 (m, 4H),2.71-2.62 (m, 4H), 2.24 (s, 6H), 1.93 (s, 4H), 1.86 (s, 2H), 1.70 (s,2H), 1.59 (s, 2H), 1.50-1.42 (m, 4H).

Example 10:3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2K by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following conditions: Column, XBridge C18 OBD Preparative Column,19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN (29.0% CH₃CNup to 33.0% in 10 min); Detector, UV 254 nm. This resulted in 302.6 mg(59%) of the title compound as a white solid. MS (m/z): 1309 [M+H]⁺. ¹HNMR (Methanol-d4, 400 MHz) δ 7.77-7.55 (m, 6H), 7.21 (d, J=1.8 Hz, 2H),7.00 (d, J=1.8 Hz, 2H), 6.15 (s, 2H), 4.89 (s, 2H), 3.89 (s, 2H),3.62-3.46 (m, 15H), 3.41 (s, 3H), 3.28 (t, J=5.4 Hz, 4H), 3.10 (q, J=5.4Hz, 8H), 3.03-2.94 (m, 3H), 2.73 (s, 4H), 2.31 (s, 5H), 1.98 (s, 2H),1.92 (s, 1H), 1.74 (s, 2H), 1.60 (d, J=10.8 Hz, 2H), 1.50-1.42 (m, 4H).

Example 11:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2L by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XSelect CSH Preparative C18 OBD Column, 19*150 mm, 5um; mobile phase, water (0.05% TFA) and CH₃CN (25.0% CH₃CN up to 32.0%in 12 min); Detector, UV 254 nm. This resulted in 278.8 mg (21%) of thetitle compound as a white solid. MS (m/z): 1163.45) [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.96-7.88 (m, 4H), 7.39-7.30 (m, 4H), 7.26 (s,2H), 6.98 (s, 2H), 6.39 (d, J=6.7 Hz, 2H), 4.35 (q, J=8.1 Hz, 2H),3.62-3.45 (m, 18H), 3.27 (t, J=5.4 Hz, 4H), 3.18-3.01 (m, 22H), 2.33 (s,6H), 1.45 (p, J=3.4 Hz, 41).

Example 12:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-[[(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2M by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm, 5 um;mobile phase, water (0.05% TFA) and CH₃CN (25% CH₃CN up to 45% in 9min); Detector, UV 254 nm. This resulted in 165.8 mg (41%) of the titlecompound as a white solid. MS (m/z): 1185 [M+H]⁺. ¹H NMR (Methanol-d4,400 MHz) δ 7.98-7.86 (m, 6H), 7.45 (s, 2H), 7.43-7.34 (m, 4H), 6.48 (s,1H), 4.50 (q, J=8.0 Hz, 2H), 3.79 (dd, J=16.6, 8.4 Hz, 2H), 3.61-3.37(m, 18H), 3.27 (t, J=5.4 Hz, 3H), 3.07 (d, J=12.7 Hz, 20H), 1.50-1.42(m, 4H).

Example 13:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Prepared according to the General Scheme above from INT-M2N by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm;mobile phase, water (10 mmol/L NH₄HCO₃) and CH₃CN (80.0% CH₃CN up to90.0% in 10 min); Detector, UV 254 nm. This resulted in 41.6 mg (7%) ofthe title compound as a white solid. MS (m/z): 1371.2 [M+100]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 8.01 (s, 2H), 7.91-7.88 (m, 4H), 7.38-7.33 (m,6H), 5.97 (d, J=5.6 Hz, 2H), 3.71 (q, J=8.0 Hz, 2H), 3.60-3.50 (m, 19H),3.33-3.26 (m, 5H), 3.12-3.08 (m, 8H), 2.37 (s, 12H), 1.50-1.31 (m, 5H).

Example 14:1-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)carbamoyl]amino)butyl]urea

Prepared according to the General Scheme above from INT-M2O by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm, 5 um;mobile phase, water (10 mmol/L NH₄HCO₃) and CH₃CN (80.0% CH₃CN up to90.0% in 10 min); Detector, UV 254 nm. This resulted in 26.5 mg (13%) ofthe title compound as a white solid. MS (m/z): 1403.15 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.87 (d, J=8.8 Hz, 4H), 7.61 (s, 2H), 7.32 (d,J=8.8 Hz, 4H), 7.19 (s, 2H), 5.97 (d, J=6.0 Hz, 2H), 3.93 (q, J=8.1 Hz,2H), 3.57-3.47 (m, 19H), 3.30 (s, 6H), 3.15-3.05 (m, 9H), 2.34 (s, 12H),1.47 (s, 4H). ¹⁹F NMR (Methanol-d4, 376 MHz) δ: 76.92 (s, 6F).

Example 15:3-[2-(2-[2-[(4-[[(1S,1S)-6-Chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2P by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XSelect CSH Preparative C18 OBD Column, 19*150 mm, 5um; mobile phase, water (0.05% TFA) and CH₃CN (24.0% CH₃CN up to 33.0%in 10 min); Detector, UV 254 nm. This resulted in 159.1 mg (34%) of thetitle compound as a white solid. MS (m/z): 1195 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.96-7.88 (m, 4H), 7.38-7.31 (m, 4H), 7.04 (d,J==1.5 Hz, 2H), 6.76 (s, 2H), 6.36 (d, 6.6 Hz, 2H), 4.91 (d, J=10.0 Hz,4H), 4.42-4.31 (m, 2H), 3.89 (s, 6H), 3.61-3.46 (m, 17H), 3.28 (t, J=5.4Hz, 4H), 3.13-3.00 (m, 21H), 1.45 (s, 5H).

Example 16:3-[2-(2-[2-[(4-[[1S,2S)-6-Chloro-2-(dimethylamino)-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Prepared according to the General Scheme above from INT-M2Q by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XBridge Preparative OBD C18 Column, 19*250 mm, 5 um;mobile phase, water (0.05% HCl) and CH₃CN (20.0% CH₃CN up to 50.0% in 8min); Detector, UV 254 nm. This resulted in 255 mg (29%) of the titlecompound as a white solid. MS (m/z): 1201.35 [M±H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.84 (q, J=3.6 Hz, 2H), 7.77 (d, J=1.6 Hz, 2H),7.52 (d, J=8.8 Hz, 2H), 7.30 (q, J=3.2 Hz, 2H), 6.99 (s, 2H), 6.59 (d,J=6.8 Hz, 2H), 4.54-4.48 (m, 2H), 3.73 (q, J=8.4 Hz, 2H), 3.62-3.51 (m,16H), 3.51-3.35 (m, 4H), 3.34-3.33 (m, 2H), 3.30 (s, 4H), 3.17-2.92 (m,16H), 2.36-2.33 (m, 6H), 1.53 (s, 1H).

Example 17:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Prepared according to the General Scheme above from INT-M2R by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XBridge Preparative C18 OBD Column, 19*150 mm, 5 um;mobile phase, water (0.05% NH₄OH) and CH₃CN (5.0% CH₃CN up to 70.0% in 1min, up to 77.0% in 6 min); Detector, UV 254/220 nm. This resulted in109.9 mg (12%) of the title compound as a white solid. MS (in/z): 1191[M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ 7.80-7.67 (m, 4H), 7.40 (d,J=8.7 Hz, 2H), 7.17-7.12 (m, 2H), 6.93 (d, J=1.8 Hz, 2H), 5.91 (d, J=6.1Hz, 2H), 3.61-3.37 (m, 19H), 3.32-3.15 (m, 6H), 3.08 (dt, J=14.5, 5.7Hz, 8H), 2.79 (dd, J=15.9, 7.9 Hz, 2H), 2.45-2.13 (m, 25H), 1.47 (p,J=3.3 Hz, 4H).

Example 18:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl] carbamoyl]amino)butyl]urea; bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2S by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XSelect CSH Preparative C18 OBD Column, 19*150 mm, 5um; mobile phase, water (0.05% TFA) and CH₃CN (22.0% CH₃CN up to 38.0%in 8 min); Detector, UV 254 nm. This resulted in 75.8 mg (24%) of thetitle compound as a white solid. MS (m/z): 1213 [M+H]⁺. ¹H NMR(Methanol-d4, 300 MHz) δ 7.94-7.75 (m, 6H), 7.56-7.39 (m, 4H), 6.54 (d,J=6.7 Hz, 2H), 4.64-4.49 (m, 2H), 3.84 (dd, J=16.7, 8.5 Fir, 2H),3.65-3.39 (m, 18H), 3.29 (d, J=5.4 Hz, 3H), 3.16-3.05 (m, 21H), 2.34 (s,6H), 1.54-1.43 (m, 4H).

Example 19:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Prepared according to the General Scheme above from INT-M2T by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XBridge Preparative C18 OBD Column, 19*150 mm, 5 um;mobile phase, water (10 mmol/L NH₄HCO₃) and CH₃CN (75% CH₃CN up to 80%in 8 min); Detector, UV 220 nm. This resulted in 42.5 mg (16%) of thetitle compound as a white solid. MS (m/z): 1399.36 [M+100]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 8.00 (d, J=1.6 Hz, 2H), 7.80 (d, J=2.0 Hz, 2H),7.78 (d, J=2.0 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.34 (s, 2H), 5.98 (d,J=5.6 Hz, 2H), 3.75 (q, 8.0 Hz, 2H), 3.59-3.50 (m, 18H), 3.33-3.26 (m,8H), 3.12-3.07 (m, 8H), 2.38 (s, 12H), 1.49 (s, 4H), 1.31 (s, 1H). ¹⁹FNMR (Methanol-d4, 400 MHz) δ: −76.94 (s, 6F).

Example 20:1-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Prepared according to the General Scheme above from INT-M2U by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm, 5 um;mobile phase, water (10 mmol/L NH₄HCO₃) and CN3CN (hold 90.0% CH₃CN in10 min); Detector, UV 254 nm. This resulted in 64.5 mg (39%) of thetitle compound as a white solid. MS (m/z): 1431.30]M+100]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.80 (d, J=2.4 Hz, 2H), 7.78 (s, 2H), 7.63 (s,2H), 7.48 (d, J=8.8 Hz, 2H), 7.19 (s, 2H), 6.01 (d, J=6.0 Hz, 2H),3.63-3.60 (m, 4H), 3.59-3.50 (m, 14H), 3.38-3.33 (m, 4H), 3.32-3.30 (m,4H), 3.19-3.12 (m, 4H), 3.10-3.07 (m, 4H), 2.97 (q, J=7.8 Hz, 2H), 2.37(s, 12H), 2.28 (s, 6H), 1.49 (s, 4H).

¹⁹F NMR (Methanol-d4, 376 MHz) δ: −75.47 (s, 6F).

Example 21:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethyl)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2V by dimerformation. Purification by preparative HPLC with the followingconditions Column, XBridge C18 OBD Preparative Column, 19*250 mm, 5 um;mobile phase, water (0.05% TFA) and CH₃CN (15% CH₃CN up to 33% in 8min); Detector, UV 254 nm. This resulted in 69.6 mg (16%) of the titlecompound as a white solid. MS (m/z): 1225 [M+H]⁺. ¹H NMR (Methanol-d4,400 MHz) δ 7.81-7.68 (m, 4H), 7.41 (d, J=8.7 Hz, 2H), 6.94 (d, J=1.6 Hz,2H), 6.70 (d, J=1.3 Hz, 2H), 6.01 (d, J=6.2 Hz, 2H), 4.61 (s, 7H), 3.86(s, 6H), 3.66-3.45 (m, 18H), 3.27 (d, J=5.7 Hz, 3H), 3.08 (dt, J=10.8,5.0 Hz, 9H), 2.80 (dd, J=16.2, 8.0 Hz, 2H), 2.49 (s, 12H), 2.26 (s, 6H),1.51-1.43 (m, 4H).

Example 22:3-[2-(2-[2-[(4-[[1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]ureadihydrochloride

Prepared according to the General Scheme above from INT-M2W by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XBridge C₁₈ OBD Preparative Column, 19*250 mm, 5 um;mobile phase, water (0.05% NH₄OH) and CH₃CN (80.0% CH₃CN up to 90.0% in8 min); Detector, UV 220 nm. The product was treated with hydrogenchloride and lyophilized. This resulted in 566 mg (62%) of the titlecompound as a white solid. MS (m/z): 1233.53 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.87-7.75 (m, 4H), 7.53 (t, 3.6 Hz, 4H), 7.11(s, 2H), 6.64 (d, J=6.8 Hz, 2H), 4.51 (td, J=8.4, 6.7 Hz, 2H), 3.72 (dd,J=16.4, 8.4 Hz, 2H), 3.65-3.48 (m, 16H), 3.41-3.31 (m, 6H), 3.16 (s,4H), 3.10 (t, J=12.4 Hz, 10H), 3.01 (s, 6H), 2.33 (s, 6H), 1.53 (dt,J=6.4, 3.6 Hz, 4H).

Example 23:3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethoxy]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2X by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XSelect CSH Preparative C18 OBD Column, 19*150 mm, 5um; mobile phase, water (0.05% NH₄OH) and CH₃CN (73% CH₃CN up to 87% in8 min); Detector, UV 254 nm. This resulted in 122.2 mg (23%) of thetitle compound as a white solid. MS (m/z): 1241.5 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.75-7.58 (m, 6H), 7.43 (d, J=1.7 Hz, 2H),7.18-7.12 (m, 2H), 5.97 (d, J=5.8 Hz, 2H), 3.61-3.46 (m, 17H), 3.35-3.20(m, 7H), 3.13-3.05 (m, 7H), 2.91 (dd, J=16.7, 7.4 Hz, 2H), 2.33 (s,12H), 1.51-1.43 (m, 4H).

Example 24:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Prepared according to the General Scheme above from INT-M2Y by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm, 5 μm;mobile phase, water (0.05% NH₄OH) and CH₃CN (50.0% CH₃CN up to 67.0% in8 min); Detector, UV 254 nm. This resulted in 132.5 mg (12%) of as awhite solid. MS (m/z): 1200 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ7.75-7.55 (m, 6H), 7.19-7.14 (m, 2H), 7.01-6.95 (m, 2H), 5.95-5.89 (d,J=5.7 Hz, 2H), 3.61-3.43 (m, 19H), 3.31-3.24 (d, J=5.4 Hz, 3H),3.24-3.05 (m, 11H), 2.86-2.75 (dd, J=16.2, 7.4 Hz, 2H), 2.36-2.27 (d,J=18.7 Hz, 18H), 1.51-1.43 (m, 4H).

Example 25:3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2Z by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm, 5 um;mobile phase, water (0.05% TFA) and CH₃CN (30.0% CH₃CN up to 62.0% in 8min); Detector, UV 254 nm. This resulted in 203.4 mg (58%) of the titlecompound as yellow oil. MS (m/z): 1371 [M+H]⁺. ¹H NMR (Methanol-d4, 400MHz) δ 7.93-7.85 (m, 4H), 7.46 (t, J=2.1 Hz, 2H), 7.34 (d, J=8.6 Hz,4H), 7.16-7.10 (m, 2H), 6.29 (dd, 15.1, 6.7 Hz, 2H), 4.00 (q J=7.6 Hz,2H), 3.62-3.24 (m, 23H), 3.20-2.99 (m, 1H), 2.92 (s, 5), 2.83 (s, 8),2.73 (s, 1H), 2.11 (s, 2H), 1.96 (d, J=12.8 Hz, 2H), 1.79 (dd, J=10.9,9.1 Hz, 4H), 1.41-1.51 (m, 4H).

Example 26:3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethoxy]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2AA by dimerformation. Purification by preparative HPLC with the followingconditions (Column, XBridge Shield RP18 OBD Column, 19*150 mm, 5 um;mobile phase, water (0.05% NH₄OH) and CH₃CN (isocratic 61.0% CH₃CN in 10min); Detector, UV 254/220 nm. This resulted in 90.6 mg (13%) of thetitle compound as a white solid. MS (m/z): 1398.9 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.80-7.67 (m, 4H), 7.50-7.38 (m, 4H), 7.16-7.10(m, 2H), 5.99 (d, J=6.0 Hz, 2H), 3.62-3.46 (m. 18H), 3.32-3.23 (m, 6H),3.07 (dt, J=29.7, 5.8 Hz, 10H), 2.91 (dd, J=16.4, 8.0 Hz, 4H), 2.27 (s,8H), 2.14 (s, 16H), 1.95 (d, J=12.6 Hz, 2H), 1.84-1.75 (m, 2H),1.64-1.52 (m, 2H), 1.52-1.44 (m, 4H), 1.28-1.15 (m, 2H).

Example 27:3-[2-(2-[2-[(4[[1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2AB by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm, 5 um;mobile phase, water (0.05% TFA) and CH₃CN (29.0% CH₃CN up to 33.0% in 10min); Detector, UV 254 nm. This resulted in 267 mg (65%) of the titlecompound as colorless oil. MS (m/z): 1407 [M+]⁺. ¹H NMR (Methanol-d4,400 MHz) δ 7.76-7.57 (m, 6H), 7.45 (d, 1=1.8 Hz, 2H), 7.22-7.17 (m, 2H),6.11 (d, 1=5.7 Hz, 2H), 3.86 (td, J=7.7, 5.8 Hz, 2H), 3.54 (dtd, J=21.8,5.5, 2.6 Hz, 17H), 3.31-3.21 (m, 5H), 3.17-2.99 (m, 13H), 2.87 (s, 16H),2.52 (t, J=9.8 Hz, 2H), 2.03 (s, 2H), 1.88 (dd, J=11.2, 6.6 Hz, 2H),1.78-1.61 (m, 4H), 1.51-1.41 (m, 4H).

Example 28:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-(1-[[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]area;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2AC by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm, 5 um;mobile phase, water (0.05% TFA) and CH₃CN (30.0% CH₃CN up to 34.0% in 9min); Detector, UV 254 nm. This resulted in 210.2 mg (18%) of the titlecompound as a white solid. MS (m/z): 1331.7 [M+H]⁺. ¹H NMR (Methanol-d4,400 MHz) δ 7.94-7.85 (m, 4H), 7.38-7.30 (m, 4H), 7.24-7.19 (m, 2H), 6.97(d, J=1.8 Hz, 2H), 6.36 (d, J=6.1 Hz, 2H), 4.15 (q, J=7.6 Hz, 2H),3.66-3.33 (m, 24H), 3.32-3.20 (m, 6H), 3.16-3.04 (m, 10H), 2.82 (s,14H), 2.31 (s, 6H), 2.18 (d, J=11.9 Hz, 2H), 2.13-2.03 (m, 2H),1.94-1.73 (m, 4H), 1.47 (h, J=3.0 Hz, 4H).

Example 29:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2AD by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm, 5 um;mobile phase, water (0.05% TFA) and CH₃CN (31.0% CH₃CN up to 36.0% in 10min); Detector, UV 254 nm. This resulted in 163.7 mg (52%) of the titlecompound as a white solid. MS (m/z): 1359.75 [M+H]⁺. ¹H NMR(Methanol-d4, 300 MHz) δ 7.80-7.65 (m, 4H), 7.43 (d, J=8.6 Hz, 2H),7.21-7.14 (m, 2H), 6.92 (d, J=1.3 Hz, 2H), 6.23 (d, J=5.7 Hz, 2H), 4.00(q, J=7.2 Hz, 2H), 3.50 (dt, J=16.7, 4.6 Hz, 19H), 3.41-3.29 (m, 4H),3.24 (d, J=5.4 Hz, 3H), 3.16 (s, 2H), 3.03 (tt, J=12.2, 6.5 Hz, 15H),2.80 (s, 14H), 2.26 (d, J=14.0 Hz, 12H), 2.10 (s, 2H), 1.96 (s, 2H),1.77 (s, 4H), 1.49-1.38 (m, 4H).

Example 30:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2AE by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm, 5 um;mobile phase, water (0.05% TFA) and CH₃CN (31.0% CH₃CN up to 36.0% in 10min); Detector, UV 254 nm. This resulted in 161.2 mg (61%) of the titlecompound as a white solid. MS (m/z): 1368 [M+H]⁺. ¹H NMR (Methanol-d4,300 MHz) δ 7.65 (dt, J=19.4, 8.6 Hz, 6H), 7.23-7.16 (m, 2H), 6.98 (d,J=1.9 Hz, 2H), 6.22 (s, 2H), 4.02 (s, 2H), 3.60-3.20 (m, 23H), 3.07 (t,J=5.5 Hz, 12H), 2.84 (s, 12H), 2.71 (s, 2H), 2.29 (s, 6H), 2.09 (s, 2H),1.95 (s, 2H), 1.75 (s, 5H), 1.44 (dd, J=4.1, 2.7 Hz, 4H).

Example 31:3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy)ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2AF by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following conditions: Column, XBridge C18 OBD Preparative Column,19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN (30.0% CH₃CNup to 52.0% in 8 min); Detector, UV 254 nm. This resulted in 122.7 mg(40%) of the title compound as a white solid. MS (m/z): 1287 [M+H]⁺. ¹HNMR (Methanol-d4, 300 MHz) δ 7.95-7.84 (m, 4H), 7.46 (d, 1.8 Hz, 2H),7.39-7.29 (m, 4H), 7.21-7.13 (m, 2H), 6.09 (d, J=6.0 Hz, 2H), 3.77-3.48(m, 19H), 3.28 (dd, J=11.7, 6.7 Hz, 6H), 3.14-2.86 (m, 10H), 1.55-1.44(m, 4H).

Example 32:3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2AG by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following conditions: Column, XBridge C18 OBD Preparative Column,19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN (35.0% CH₃CNup to 55.0% in 8 min); Detector, UV 254 nm. This resulted in 183.2 mg(60%) of title compound as a white solid. MS (m/z): 1316.2 [M+H]⁺. ¹HNMR (Methanol-d4, 400 MHz) δ 7.82-7.70 (m, 4H), 7.54-7.43 (m, 5H),7.17-7.12 (m, 2H), 6.09 (d, J=6.1 Hz, 2H), 3.72 (td, J=7.9, 6.0 Hz, 2H),3.64-3.49 (m, 16H), 3.28 (dt, J=17.6, 5.2 Hz, 13H), 3.16-2.79 (m, 19H),2.29 (s, 6H), 1.49 (p, J=3.4 Hz, 4H).

Example 33:3-[2-(2-[2-[4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfanamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2AH by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following conditions: Column, XBridge C18 OBD Preparative Column,19*250 mm; mobile phase, water (0.05% TFA) and CH₃CN (22.0% CH₃CN up to42.0% in 11 min); Detector, UV 254 nm. This resulted in 419.2 mg (69%)of the title compound as a white solid. MS (m/z): 1323 [M+H]. ¹H NMR(Methanol-d4, 300 MHz) δ 7.75-7.52 (m, 6H), 7.42 (d, J=1.7 Hz, 2H),7.20-7.12 (m, 2H), 6.04 (d, J=5.9 Hz, 2H), 3.72 (td, J=7.7, 5.8 Hz, 2H),3.60-3.43 (m, 16H), 3.29-3.12 (m, 13H), 3.13-2.72 (m, 19H), 1.44 (p,J=3.3 Hz, 4H).

Example 34:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2AI by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following conditions: Column, XBridge C18 OBD Preparative Column,19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN (20% CH₃CN upto 38% in 8 min); Detector, UV 254 nm. This resulted in 288.6 mg (64%)of the title compound as a white solid. MS (m/z): 1245 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.91-7.82 (m, 4H), 7.34-7.25 (m, 4H), 7.20-7.14(m, 2H), 6.98 (d, J=1.9 Hz, 2H), 6.00 (d, J=5.8 Hz, 2H), 3.69-3.46 (m,18H), 3.32-3.03 (m, 22H), 2.97-2.79 (m, 10H), 2.29 (s, 6H), 1.47 (p,J=3.3 Hz, 4H).

Example 35:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2AJ by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following conditions: Column, XBridge C18 OBD Preparative Column,19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN (22% CH₃CN upto 38% in 10 min); Detector, UV 254 nm. This resulted in 303.9 mg (66%)of the title compound as a white solid. MS (m/z): 638.15 [M/2+H]⁺. ¹HNMR (Methanol-d4, 400 MHz) δ 7.80-7.67 (m, 4H), 7.43 (d, J=8.7 Hz, 2H),7.20-7.14 (m, 2H), 6.96 (d, J=1.8 Hz, 2H), 6.02 (d, J=5.9 Hz, 2H),3.71-3.61 (m, 2H), 3.61-3.46 (m, 16H), 3.32-3.15 (m, 14H), 3.08 (dt,J=15.4, 5.7 Hz, 8H), 2.89 (ddt, J=22.8, 13.6, 6.0 Hz, 10H), 2.28 (d,J=16.7 Hz, 12H), 1.47 (p, J=3.2 Hz, 4H).

Example 36:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M2AK by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following condition: Column, XBridge C18 OBD Preparative Column,19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN (30.0% CH₃CNup to 38.0% in 11 min); Detector, UV 254 nm. This resulted in 358.1 mg(59%) of the title compound as a white solid. MS (in/z): 1281 [M+H]⁺. ¹HNMR (Methanol-d4, 300 MHz) δ 7.74-7.51 (m, 6H), 7.20-7.13 (m, 2H), 6.99(d, J=1.8 Hz, 2H), 6.01 (d, J=5.6 Hz, 2H), 3.69 (td, J=7.6, 5.6 Hz, 2H),3.60-3.42 (m, 16H), 3.29-3.01 (m, 22H), 2.88 (tq, J=11.5, 6.9, 5.7 Hz,10H), 2.27 (s, 6H), 1.50-1.39 (m, 4H).

Alternate Route to Monomer Synthesis

Step A: To a round-bottom flask was added bromoaminoindanol INT-18 (1equiv), phenol INT-L6 (1.2 equiv), tetrahydrofuran (0.43 M), and PPh3(1.5 equiv). The flask was heated to 40-45° C. followed by the additionof DIAD (1.5 equiv) dropwise over 15-20 min. The resulting slurry wasstirred for 1 h at 40° C. in an oil bath. The resulting mixture wasconcentrated under vacuum and diluted with CH₂Cl₂. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(0-80%) providing the sulfonamide INT-M3.

Step B: To a round-bottom flask was added INT-M3 (I equiv), NMP (0.1 M),Pd(PPh3)₄ (0.1 equiv), and Zn(CN)₂ (0.6 equiv). The resulting solutionwas stirred overnight at 100° C. in an oil bath. The resulting solutionwas extracted with 3× ethyl acetate. The organic layers were combined,washed with 3× brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (0-80%) providing the 4-cyanoaminoindanols INT-M4.

Step C: To a round-bottom flask was added aminoindanol INT-M4 (1 equiv),tetrahydrofuran (0.066 M), and sodium hydroxide (3 M, 7.5 equiv). Theresulting slurry was stirred for 1 h at room temperature. The resultingsolution was extracted with 4× ethyl acetate. The organic layers werecombined, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with CH₂Cl₂/methanol (5:1) providing the amine monomer INT-M5.

The following intermediates are made by applying the above procedures tothe appropriate starting aminoindanols INT-I8 and linkers INT-L6:

General Procedure for Dimer Product Synthesis: Conversion of monomersINT-M5 proceeded via the same sequence as the conversion of INT-M2 tothe desired dimer Products 1 (with or without the follow-onBoc-deprotection as necessary).

Example 37:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-M-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Prepared according to the General Scheme above from INT-M5A by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XBridge Preparative C18 OBD Column, 19*150 mm 5 um;mobile phase, water (0.05% NH₄OH) and CH₃CN (55.0% CH₃CN up to 59.0% in7 min); Detector, UV 254/220 nm. This resulted in 64.8 mg (6%) of thetitle compound as a white solid. MS (m/z): 1223.6 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.77 (d, J=1.8 Hz, 2H), 7.75-7.62 (m, 6H),7.53-7.47 (m, 2H), 6.00 (d, J=5.8 Hz, 2H), 3.65 (q, J=7.3 Hz, 2H),3.60-3.52 (m, 8H), 3.50 (td, J=5.5, 2.1 Hz, 8H), 3.31 (m, 4H), 3.28 (d,5.4 Hz, 3H), 3.15-3.04 (m, 10H), 2.36 (s, 12H), 1.47 (p, J=3.2 Hz, 4H).

Example 38:3-[2-(2-[2-[(4-[[(1S,2S)-21(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M5B by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following conditions: Column, XBridge C18 OBD Preparative Column,19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN (29.0% CH₃CNup to 33.0% in 10 min); Detector, UV 254 nm. This resulted in 302.6 mg(59%) of the title compound as a white solid. MS (m/z): 1331 [M+H]⁺. ¹HNMR (Methanol-d4, 400 MHz) δ 7.80 (d, J=1.9 Hz, 2H), 7.77-7.58 (m, 7H),7.54 (d, J=2.3 Hz, 2H), 6.14-6.04 (m, 2H), 3.84 (d, J=16.5 Hz, 2H), 3.54(dtd, J=23.1, 5.3, 3.1 Hz, 17H), 3.38 (dd, J=18.7, 7.4 Hz, 5H), 3.19(dt, J=75.2, 5.4 Hz, 15H), 2.98 (s, 3H), 2.76 (s, 2H), 2.61 (s, 5H),1.93 (s, 3H), 1.85 (s, 2H), 1.65 (s, 2H), 1.56 (s, 3H), 1.47 (p, J=3.3Hz, 4H).

Example 39:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M5C by dimerformation. Purification by preparative HPLC with the followingconditions (Column, XBridge Shield RP18 OBD Column, 19*150 mm, 5 um;mobile phase, water (0.05% NH₄OH) and CH₃CN (47.0% CH₃CN up to 48.0% in15 min); Detector, UV 254/220 nm. This resulted in 52.9 mg (10%) of thetitle compound as a white solid. MS (m/z): 1381.85 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.80-7.67 (m, 6H), 7.53-7.44 (m, 4H), 6.02 (d,J=6.0 Hz, 2H), 3.69-3.46 (m, 20H), 3.39 (dd, J=16.7, 8.0 Hz, 2H), 3.28(d, J=5.4 Hz, 2H), 3.15-2.99 (m, 12H), 2.92 (d, J=11.1 Hz, 2H), 2.28 (s,8H), 2.15 (s, 16H), 1.95 (d, J=12.9 Hz, 2H), 1.80 (dt, J=13.8, 3.4 Hz,2H), 1.65-1.43 (m, 6H), 1.23 (ddt, J=20.4, 12.3, 6.6 Hz, 2H).

Example 40:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M5D by dimerformation. Purification by preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm, 5 um;mobile phase, water (0.05% TFA) and CH₃CN (30.0% CH₃CN up to 40.0% in 8min); Detector, UV 254 nm. This resulted in 334 mg (73%) of the titlecompound as a white solid. MS (m/z): 1387 [M+H]⁺. ¹H NMR (Methanol-d4,400 MHz) δ 7.80 (d, J=1.9 Hz, 2H), 7.77-7.59 (m, 6H), 7.54 (dd, J=1.8,0.8 Hz, 2H), 6.16 (d, J=6.0 Hz, 2H), 3.97 (q, J=7.6 Hz, 2H), 3.54 (dtd,J=22.5, 5.4, 2.9 Hz, 17H), 3.46-3.17 (m, 13H), 3.14-3.05 (in, 8H), 2.87(s, 16H), 2.55 (t, J=9.8 Hz, 2H), 2.06 (t, J=11.1 Hz, 2H), 1.90 (dd,J=10.2, 5.1 Hz, 2H), 1.69 (q, J=10.9, 10.0 Hz, 4H), 1.53-1.41 (m, 4H).

Example 41:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M5E by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following conditions: Column, XBridge Preparative C18 OBD Column,19*150 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN (28.0% CH₃CNup to 29.0% in 7 min); Detector, UV 254/220 nm. This resulted in 326.1mg (53%) of the title compound as a white solid. MS (m/z): 1267 [M+H]⁺.¹H NMR (Methanol-d4, 400 MHz) δ 7.92-7.89 (m, 4H), 7.77 (d, J=1.9 Hz,2H), 7.47 (dd, J=1.8, 0.9 Hz, 2H), 7.37-7.28 (m, 4H), 6.09 (d, J=6.1 Hz,2H), 3.76 (td, J=7.9, 6.0 Hz, 2H), 3.62-3.46 (m, 16H), 3.38 (dd, J=16.8,8.0 Hz, 2H), 3.26 (dt, J=14.7, 5.2 Hz, 11H), 3.20-3.03 (m, 10H), 2.88(qt, J=12.8, 4.5 Hz, 8H), 1.51-1.43 (m, 4H).

Example 42:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy]ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M5F by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following conditions: Column, XSelect CSH Preparative C18 OBDColumn, 19*150 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN(20.0% CH₃CN up to 40.0% in 10 min); Detector, UV 254 nm. This resultedin 361.4 mg (59%) of the title compound as a white solid. MS (m/z):1297.70 [M+H]⁺. ¹H NMR (Methanol-d4, 300 MHz) δ 7.79-7.64 (m, 6H),7.48-7.39 (m, 4H), 6.08 (d, J=6.1 Hz, 2H), 3.76 (td, J=7.9, 6.0 Hz, 2H),3.60-3.30 (m, 19H), 3.29-2.75 (m, 29H), 2.24 (s, 6H), 1.50-1.39 (m, 4H).

Example 43:3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Prepared according to the General Scheme above from INT-M5G by dimerformation and Boc-deprotection. Purification by preparative HPLC withthe following conditions: Column, XBridge C18 OBD Preparative Column,19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN (20.0% CH₃CNup to 42.0% in 8 min); Detector, UV 254 nm. This resulted in 355.1 mg(81%) of the title compound as a white solid. MS (m/z): 1303 [M+H]⁺. ¹HNMR (Methanol-d4, 300 MHz) δ 7.80-7.47 (m, 10H), 6.06 (d, J=6.1 Hz, 2H),3.80 (td, J=7.9, 6.0 Hz, 2H), 3.51 (dtd, J=17.3, 5.2, 2.4 Hz, 16H),3.42-3.01 (m, 24H), 2.86 (tq, J=13.2, 7.8, 6.3 Hz, 8H), 1.50-1.39 (m,4H).

Scheme for Hydroxymethylpyrrolidine Linker Synthesis:

Step A: To a 250-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added tert-butyl (3,S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (500 mg, 2.48 mmol, 1equiv), CH₂Cl₂ (5 mL), and trifluoroacetic acid (1 ml). The resultingsolution was stirred for 1 h at room temperature in an oil bath. Theresulting mixture was concentrated under vacuum. This resulted in 250 mg(99%) of (3S)-pyrrolidin-3-ylmethanol trifluoroacetic acid salt as brownoil which was used directly in Step B.

Step B: To a 50-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added (3S)-pyrrolidin-3-ylmethanol (125mg, 1.24 mmol, 1 equiv), CH₂Cl₂ (5 mL), and trimethylamine (0.5 mL, 3equiv). This was followed by the dropwise addition of a solution of4-(benzyloxy)-3-methylbenzene-1-sulfonyl chloride (INT-L3 whereR¹=m-methyl, 360 mg, 1.21 mmol, 0.98 equiv) in CH₂Cl₂ (5 mL). Theresulting solution was stirred for 1 h at room temperature. Theresulting slurry was extracted with 3×20 mL of ethyl acetate. Theorganic layers were combined, washed with 1×20 mL of brine, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1/10) providing 400 mg (90%) of[(3S)-1-[[4-(benzyloxy)-3-methylbenzene]sulfonyl]pyrrolidin-3-yl]methanolas a yellow oil.

Step C: To a 250-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added sodium hydride (763 mg, 31.79mmol, 3 equiv), N,N-dimethylformamide (60 mL), INT-SM2 (2.3 g, 6.36mmol, 1 equiv), 15-crown-5 (3.8 mL, 3 equiv), and1-[2-(2-azidoethoxy)ethoxy]sulfonyl-4-methylbenzene (2.7 g, 9.46 mmol,1.5 equiv). The resulting solution was stirred overnight at roomtemperature. The reaction was then quenched by the addition of water andextracted with 3×50 mL of ethyl acetate. The organic layers combined,washed with 4×100 mL of brine, dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1/3) providing 1.2g (40%) of(3S)-3-[[2-(2-azidoethoxy)ethoxy]methyl]-1-[[4-(benzyloxy)-3-methylbenzene]sulfonyl]pyrrolidine(INT-SM3) as a yellow oil.

Step D: To a 100-mL round-bottom flask purged and maintained with aninert atmosphere of hydrogen was added azide INT-SM3 (1.2 g, 2.53 mmol,1 equiv), ethyl acetate (6 mL), methanol (6 mL), and palladium on carbon(500 mg). The resulting slurry was stirred for 2 h at room temperature.The resulting mixture filtered to remove palladium and the filtrateconcentrated under vacuum. This resulted in 740 mg (82%) of4-[(3S)-3-[[2-(2-aminoethoxy)ethoxy]methyl]pyrrolidine-1-sulfonyl]-2-methylphenol(INT-SM4) as a yellow oil.

Step E: To a 50-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added amine INT-SM4 (740 mg, 2.06 mmol,1 equiv), methanol (8 mL), triethylamine (41.7 mg, 0.41 mmol, 0.20equiv), and ethyl 2,2,2-trifluoroacetate (0.75 mL, 3 equiv). Theresulting solution was stirred for 2 h at room temperature. Theresulting slurry was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1/1)providing 800 mg (85%) of2,2,2-trifluoro-N-[2-(2-[[(3S)-1-[(4-hydroxy-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]acetamide(INT-SM5) as a yellow oil.

The R-enantiomer of INT-SM5 was generated from the analogous procedurebeginning with tert-butyl(3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate. This provided INT-RM5:

Scheme for Hydroxymethylpyrrolidine Dimer Product Synthesis:

Step A: To a 50-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added phenol INT-SM5 (300 mg, 0.66mmol, 1 equiv), aminoindanol INT-18C (162.47 mg, 0.66 mmol, 1 equiv),and tetrahydrofuran (1.5 mL). This was followed by the addition of PPh₃(260 mg, 0.99 mmol, 1.5 equiv) at 40° C. followed by the dropwiseaddition of DIAD (0.195 mL, 1.5 equiv) with stirring at 40° C. Theresulting solution was stirred for 1 h at 40° C. in an oil bath. Theresulting slurry was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (2/1)providing 400 mg (89%) ofN-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-2,2,2-trifluoroacetamide(INT-SMG) as a yellow oil.

Step B: To a 250-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was added INT-SMG (400 mg, 0.59 mmol, 1equiv) and methanol (4 mL) followed by the addition of sodium hydroxide(3 M, 1 mL). The resulting slurry was stirred for 1 h at GO ° C. in anoil bath. The resulting solution was extracted with 3×20 mL of ethylacetate. The organic layers combined, washed with 1×20 mL of brine,dried over anhydrous sodium sulfate, filtered, and concentrated undervacuum. The residue was applied onto a silica gel column withCH₂Cl₂/methanol (5/1) providing 300 mg (87%) of(1S,2S)-1-[4-[(3S)-3-[[2-(2-aminoethoxy)ethoxy]methyl]pyrrolidine-1-sulfonyl]-2-methylphenoxy]-4,6-dichloro-N,N-dimethyl-2,3-dihydro-1H-inden-2-amine(INT-SM7) as a yellow oil.

Step C: To a 50-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added amine INT-SM7 (300 mg, 0.51 mmol,1 equiv), N,N-dimethylformamide (3.4 mL), and 1,4-diisocyanatobutane(0.029 mL, 0.45 equiv). The resulting solution was stirred for 1 h at60° C. in an oil bath. The resulting mixture was concentrated undervacuum. The crude product was purified by preparative HPLC with thefollowing conditions: Column, XBridge Shield RP18 OBD Column, 19*150 mm,5 um; mobile phase, water (0.05% TFA) and CH₃CN (35.0% CH₃CN up to 48.0%in 8 min); Detector, UV 254 nm.

Example 44:3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; bis(trifluoroacetic acid)

Steps A-C provided 221.4 mg (28%) of the title compound as a whitesolid. MS (m/z): 1313 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ 7.82-7.70(m, 4H), 7.57-7.47 (m, 4H), 7.10-7.04 (m, 2H), 6.49 (d, J=6.7 Hz, 2H),4.50 (td, J=8.4, 6.6 Hz, 2H), 3.70 (dd, J=16.5, 8.6 Hz, 2H), 3.57-3.53(m, 4H), 3.53-3.44 (m, 8H), 3.40-3.31 (m, 6H), 3.29-3.16 (m, 10H),3.12-3.07 (m, 6H), 3.05 (s, 12H), 2.38 (p, J=6.7 Hz, 2H), 2.32 (s, 6H),1.92 (td, J=12.8, 7.4 Hz, 2H), 1.65-1.51 (m, 2H), 1.50-1.42 (m, 4H).

Example 45:3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy]ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Beginning with R-enantiomer INT-RM5 and INT-18C, Steps A-C provided 306mg (67%) of the title compound as a white solid. MS (m/z): 1314 [M+H]⁺.¹H NMR (Methanol-d4, 400 MHz) δ 7.82-7.70 (m, 4H), 7.56-7.48 (m, 4H),7.10-7.04 (m, 2H), 6.51 (d, J=6.7 Hz, 2H), 4.49 (td, J=8.5, 6.6 Hz, 2H),3.70 (dd, J=16.5, 8.6 Hz, 2H), 3.59-3.44 (m, 12H), 3.41-3.03 (m, 33H),2.32 (s, 8H), 1.99-1.86 (m, 2H), 1.58 (dq, J=14.5, 7.4 Hz, 2H),1.49-1.41 (m, 4H).

Scheme for Cyano-containing Hydroxymethylpyrrolidine Dimer ProductSynthesis: Example 46:3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Step A: To a 50-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was added phenol INT-SM5 (500 mg, 1.1mmol, 1 equiv), aminoindanol INT-I8B (320 mg, 1.1 mmol, 1 equiv),tetrahydrofuran (2.5 mL), and PPh₃ (433 mg, 1.65 mmol, 1.5 equiv).Heating at 40° C. in an oil bath DIAD (0.33 mL, 1.5 equiv) was addeddropwise with stirring. The resulting solution was stirred for 1 h. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (2/1)providing 700 mg (88%) ofN-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4-bromo-6-chloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-2,2,2-trifluoroacetamide(INT-SM8) as a yellow oil.

Step B: To a 50-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added bromoaminoindanol INT-SM8 (640mg, 0.88 mmol, 1.00 equiv), NMP (7 mL), Zn(CN)₂ (62 mg, 0.60 equiv), andPd(PPh₃)₄ (102 mg, 0.09 mmol, 0.10 equiv). The resulting solution wasstirred overnight at 100° C. in an oil bath. The resulting slurry wasdiluted with water and extracted with 3×20 mL of ethyl acetate. Theorganic layers were combined, washed with 3×20 mL of brine, and dried inan oven under reduced pressure. The residue was applied onto a silicagel column with ethyl acetate/petroleum ether (1/5) providing 550 mg(93%) ofN-[2-(2-[[(3S)-1-[[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-2,2,2-trifluoroacetamide(INT-SM9) as a yellow oil.

Step C: To a 100-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added INT-SM9 (550 mg, 0.82 mmol, 1equiv) and methanol 7 mL) followed by the addition of sodium hydroxide(3 M_((aq)), 1 mL). The resulting solution was stirred for 5 h at roomtemperature. The reaction was then quenched by the addition of water andextracted with 3×20 mL of ethyl acetate. The organic layers werecombined, washed with 1×20 mL of brine, filtered, and concentrated to asolid under vacuum. The solid was dried in an oven under reducedpressure. The residue was applied onto a silica gel column withCH₂Cl₂/methanol (5/1) providing 460 mg (98%) of(1S,2S)-1-[4-[(3S)-3-[[2-(2-aminoethoxy)ethoxy]methyl]pyrrolidine-1-sulfonyl]-2-methylphenoxy]-6-chloro-2-(dimethylamino)-2,3-dihydro-1ii-indene-4-carbonitrile (INT-SM10) as a yellow oil.

Step D: To a 50-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added amine INT-SM10 (460 mg, 0.80mmol, 1 equiv), N,N-dimethyl formamide (5.5 mL), and1,4-diisocyanatobutane (52.4 mg, 0.37 mmol, 0.47 equiv). The resultingsolution was stirred for 1 h at 60° C. in an oil bath. The resultingmixture was concentrated under vacuum. The crude product was purified byPreparative HPLC with the following conditions: Column, XBridge C18 OBDPreparative Column, 19*250 mm, 5 um; mobile phase, water (0.05% TFA) andCH₃CN (32.0% CH₃CN up to 54.0% in 8 min); Detector, UV 254 nm.

Example 46:3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Steps A-D provided 130.6 mg (11%) of the title compound as a whitesolid. MS (m/z): 1295 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ 7.89 (d,J=1.9 Hz, 2H), 7.85-7.70 (m, 4H), 7.54 (d, J=8.7 Hz, 2H), 7.44-7.37 (m,2H), 6.56 (d, J=6.6 Hz, 2H), 4.63-4.49 (m, 2H), 3.83 (dd, J=16.7, 8.5Hz, 2H), 3.61-3.04 (m, 46H), 2.33 (s, 8H), 1.94 (dt, J=13.5, 6.8 Hz,2H), 1.59 (dd, J=13.1, 7.2 Hz, 2H), 1.47 (dd, J=3.7, 3.0 Hz, 4H).

Example 47:3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Beginning with R-enantiomer INT-RM5 and INT-18B, Steps A-D provided 248mg (27%) of the title compound as a white solid. MS (m/z): 1293 [M+H]⁺.¹H NMR (Methanol-d4, 400 MHz) a 7.78-7.65 (m, 6H), 7.51 (d, J=8.7 Hz,2H), 7.45-7.40 (m, 2H), 6.00 (d, J−6.1 Hz, 2H), 3.64-3.45 (m, 14H),3.44-3.14 (m, 14H), 3.14-3.02 (m, 8H), 2.35 (s, 12H), 2.27 (s, 6H), 1.91(dtd, J=12.8, 7.5, 5.4 Hz, 2H), 1.57 (dq, J=14.3, 7.3 Hz, 2H), 1.47 (p,J=3.3 Hz, 4H).

Scheme for Pyridinyl Linker Synthesis:

Step A: To a 50-mL round-bottom flask was added N,N-dimethylformamide(12 mL), sodium hydride (331.2 mg, 13.8 mmol, 5 equiv),4-chloropyridine-2-carbonitrile (574.1 mg, 4.14 mmol, 1.5 equiv),sulfonamide INT-SM2 (1.0 g, 2.77 mmol, 1 equiv). The resulting solutionwas stirred for 1.5 h at room temperature. The reaction was thenquenched by the addition of 20 mL of NR₄Cl and extracted with 3×100 mLof ethyl acetate. The organic layers were combined, washed with 1×100 mLof brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:1) providing 570 mg (44%)of4-[[(3S)-1-[[4-(benzyloxy)-3-methylbenzene]sulfonyl]pyrrolidin-3-yl]methoxy]pyridine-2-carbonitrile(INT-SP1) as a white solid.

Step B: To a 100-mL round-bottom flask purged and maintained with aninert atmosphere of H₂ was added INT-SP1 (660 mg, 1.42 mmol, 1 equiv),ethanol (20 mL), and Raney Ni (660 mg). The resulting solution wasstirred for overnight at room temperature. The resulting mixture wasfiltered and concentrated under vacuum providing 520 mg (78%) of(4-[[(3S)-1-[[4-(benzyloxy)-3-methylbenzene]sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methanamine(INT-SP2) as a brown solid.

Step C: To a 100-mL round-bottom flask was added amine INT-SP2 (520 mg,1.11 mmol, 1 equiv), 1:1 tetrahydrofuran:H₂O (20 mL), and sodiumcarbonate (588.3 mg, 5.55 mmol, 5 equiv). This was followed by theaddition of a solution of Boc₂O (485 mg, 2.22 mmol, 2 equiv) intetrahydrofuran (5 mL) dropwise with stirring at 5-10° C. in 5 min. Theresulting solution was stirred for 2 h at room temperature. Theresulting slurry was extracted with 3×100 mL of ethyl acetate. Theorganic layers were combined, washed with 1×100 mL of brine, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was applied onto a silica gel column with CH₂Cl₂/methanol (5:1)providing 520 mg (82%) of tert-butylN-[(4-[[(3S)-1-[[4-(benzyloxy)-3-methylbenzene]sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamate(INT-SP3) as a white solid.

Step D: To a 100-mL round-bottom flask purged and maintained with aninert atmosphere of hydrogen was added a solution of INT-SP3 (520 mg,0.92 mmol, 1 equiv), ethyl acetate (10 mL), and 10% Pd/C (520 mg). Theresulting slurry was stirred for 1 h at room temperature. The solidswere filtered out and the filtrate concentrated under vacuum providing420 mg (96%) of tert-butyl N-[(4-[[(3,S)-1-[(4-hydroxy-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamate(INT-SP4) as a white solid.

The R-enantiomer of INT-SP4 was generated from the analogous procedurebeginning with tert-butyl(3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate. This provided INT-RP4:

Scheme for Pyridinyl Dimer Product Synthesis: Example 48:3-[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea

Step A: To a 7-mL round-bottom flask was added phenol INT-SP4 (170 mg,0.36 mmol, 1 equiv), aminoindanol INT-I8C (96.4 mg, 0.39 mmol, 1.1equiv), tetrahydrofuran (0.83 mL), and PPh₃ (140.1 mg, 0.53 mmol, 1.50equiv). Heating at 40° C. in an oil bath DIAD (0.11 mL) was addeddropwise with stirring over 15 min. The resulting solution was stirredfor 1 h at 40-45° C. in an oil bath. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (100%) providing200 mg (80%) of tert-butylN-[(4-[[(3S)-1-[1(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamate(INT-SP5) as a yellow oil.

Step B: To a 100-mL round-bottom flask was added INT-SP5 (200 mg, 0.28mmol, 1 equiv), CH₂Cl₂ (15 mL), and trifluoroacetic acid (5 mL). Theresulting solution was stirred for 1 h at room temperature. The pH valueof the solution was adjusted to 9.0-10.0 with sodium bicarbonate (100%)and the slurry extracted with 3×100 mL of ethyl acetate. The organiclayers were combined, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with CH₂Cl₂/methanol (5:1) providing 153 mg (89%) of(1S,2S)-1-[4-[(3S)-([[2-(aminomethyl)pyridin-4-yl]oxy]methyl)pyrrolidine-1-sulfonyl]-2-methylphenoxy]-4,6-dichloro-N,N-dimethyl-2,3-dihydro-1H-inden-2-amine(INT-SP6) as a white solid.

Step C: To a 25-mL round-bottom flask was added amine INT-SP6 (153 mg,0.25 mmol, 2.08 equiv), 1,4-diisocyanatobutane (17 mg, 0.12 mmol, 1equiv), and N,N-dimethylformamide (1.7 mL). The resulting solution wasstirred for 1 h at 60° C. in an oil bath. The solids were filtered out.The crude product was purified by Preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm, 5 um;mobile phase, water (0.05% NH₄OH) and CH₃CN (85% CH₃CN up to 90% in 8min); Detector, UV 254 nm.

Example 48:3-[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea

Steps A-C provided 62.3 mg (38%) of the title compound as a white solid.MS (m/z): 1351 [M+H]⁺. ¹H NMR (Methanol-d4, 300 MHz) δ 8.15 (d, J=5.9Hz, 2H), 7.77-7.60 (m, 4H), 7.49-7.34 (m, 4H), 7.06 (d, J=1.1 Hz, 2H),6.82 (d, J=2.5 Hz, 2H), 6.67 (dd, J=5.9, 2.5 Hz, 2H), 5.93 (d, J=6.2 Hz,2H), 4.29 (s, 4H), 4.00 (s, 2H), 3.88 (dd, J=9.4, 6.0 Hz, 2H), 3.73 (t,J=8.7 Hz, 2H), 3.50-3.29 (m, 10H), 3.28-3.10 (m, 6H), 2.87 (dd, J=16.4,7.7 Hz, 1H), 2.58 (s, 4H), 2.29 (s, 11H), 2.16 (s, 6H), 1.49 (s, 4H).

Example 49:3-[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea.Beginning with R-enantiomer INT-RP4 and INT-18B

Steps A-C provided 54.3 mg (31%) of the title compound as a white solid.MS (m/z): 1351 [M+H]⁺. ¹H NMR (Methanol-d4, 300 MHz) δ 8.18 (d, J=5.9Hz, 1H), 7.77-7.61 (m, 2H), 7.49-7.33 (m, 2H), 7.04 (d, J=1.1 Hz, 1H),6.83 (d, J=2.4 Hz, 1H), 6.71 (dd, J=5.9, 2.5 Hz, 1H), 5.92 (d, J=5.8 Hz,1H), 4.56 (s, 5H), 4.30 (s, 2H), 3.96-3.73 (m, 2H), 3.51-3.32 (m, 3H)3.27-3.08 (m, 5H), 2.87 (dd, J=16.6, 7.7 Hz, 1H), 2.30 (s, 7H),2.63-2.52 (m, 1H), 2.19 (s, 4H), 2.00 (d, J=7.9 Hz, 2H), 1.67 (dd,J=13.2, 71 Hz, 1H), 1.50 (s, 4H), 1.30 (d, J=25.9 Hz, 6H), 0.86 (d,J=6.2 Hz, 2H).

Scheme for Cyano-containing Pyridinyl Dimer Product Synthesis: Example50:3-[4-[[(3S)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[4-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea

Step A: To a 7-mL round-bottom flask was added phenol INT-SP4 (250 mg,0.52 mmol, 1 equiv), aminoindanol INT-18B (167.36 mg, 0.58 mmol, 1.1equiv), tetrahydrofuran (1.22 mL), and PPh₃ (206.2 mg, 0.79 mmol, 1.50equiv). Heating at 40° C. in an oil bath DIAD (0.16 mL) was addeddropwise with stirring. The resulting solution was stirred for 1 h at40-45° C. in an oil bath. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column withdichloromethane/methanol (5:1) providing 300 mg (76%) of tert-butylN-[(4-[[3S)-1-[(4-[[(1S,2S)-4-bromo-6-chloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamate(INT-SP7) as a white solid.

Step B: To a 50-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added bromoaminoindanol INT-SP7 (300mg, 0.40 mmol, 1 equiv), Zn(CN)₂ (28.16 mg, 0.24 mmol, 0.60 equiv), NMP(5 mL), and Pd(PPh3)₄ (46.22 mg, 0.04 mmol, 0.10 equiv). The resultingsolution was stirred for overnight at 100° C. in an oil bath. Theresulting solution was extracted with 3×100 mL of ethyl acetate. Theorganic layers were combined, washed with 3×100 mL of brine, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was applied onto a silica gel column withdichloromethane/methanol (10:1) providing 300 mg (crude) of tort-butylN-[(4-([[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamate(INT-SP8) as a white solid, used without further purification in Step C.

Step C: To a 100-mL round-bottom flask was added INT-SP8 (220 mg, 0.32mmol, 1 equiv) and 3:1 CH₂Cl₂:TFA (20 mL). The resulting solution wasstirred for 1 h at room temperature. The pH value of the solution wasadjusted to 9.0-10.0 with sodium bicarbonate and extracted with 3×100 mLof ethyl acetate. The organic layers were combined, dried over anhydroussodium sulfate, filtered, and concentrated under vacuum. The residue wasapplied onto a silica gel column with CH₂Cl₂/methanol (5:1) providing187 mg (crude) of(1S,2S)-1-[4-[(3S)-3-([[2-(aminomethyl)pyridin-4-yl]oxy]methyl)pyrrolidine-1-sulfonyl]-2-methylphenoxy]-6-chloro-2-(dimethylamino)-2,3-dihydro-1H-indene-4-carbonitrile(INT-SP9) as a white solid.

Step D: To a 7-mL round-bottom flask was added amine INT-SP9 (187 mg,0.31 mmol, 2.22 equiv), N,N-dimethylformamide (2.1 mL), and1,4-diisocyanatobutane (19.8 mg, 0.14 mmol, 1 equiv). The resultingsolution was stirred for 1 h at 60° C. in an oil bath. The solids werefiltered out. The crude product was purified by preparative HPLC withthe following conditions: Column, X Bridge C18 OBD Preparative Column,19*250 mm, 5 um; mobile phase, water (0.05% NH₄OH) and CH₃CN (55% CH₃CNup to 57% in 8 min); Detector, UV 254 nm.

Example 50:3-[(4-[[(3S)-1[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea

Steps A-D provided 64.5 mg (34%) of the title compound as a white solid.MS (m/z): 1333 [M+H]⁺. ¹H NMR (Methanol-d4, 300 MHz) δ 8.16 (d, J=5.7Hz, 2H), 7.77-7.61 (m, 6H), 7.52-7.36 (m, 4H), 6.82 (d, J=2.3 Hz, 2H),6.73-6.64 (m, 2H), 5.95 (d, J=6.0 Hz, 2H), 4.29 (s, 4H), 3.88 (dd,J=9.5, 6.0 Hz, 2H), 3.74 (dd, J=9.5, 7.7 Hz, 2H), 3.61-3.28 (m, 7H),3.28-2.97 (m, 11H), 2.57 (dt J=14.1, 7.0 Hz, 2H), 2.30 (s, 12H), 2.18(s, 6H), 2.10-1.92 (m, 2H), 1.68 (dq, J=14.0, 7.2 Hz, 2H), 1.55-1.44 (m,4H).

Example 51:3-[(4-[[(3R)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl]methyl]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea

Beginning with R-enantiomer INT-RP4 and INT-18B, Steps A-D provided 39.6mg (37%) of the title compound as a white solid. MS (m/z): 1333 [M+H]⁺.¹H NMR (DMSO-d6, 400 MHz) δ 8.23 (d, J=5.6 Hz, 2H), 7.99 (d, J=1.9 Hz,2H), 7.70-7.60 (m, 4H), 7.58-7.49 (m, 4H), 6.76-6.66 (m, 4H), 6.32 (t,J=5.8 Hz, 2H), 6.09 (t, J=5.6 Hz, 2H), 5.93 (d, J=5.4 Hz, 2H), 4.18 (d,J=5.7 Hz, 4H), 3.80 (ddd, J=32.6, 9.6, 6.8 Hz, 4H), 3.52 (dd, J=7.7, 5.8Hz, 2H), 3.36-2.93 (m, 16H), 2.49 (s, 210, 2.16 (d, J=11.9 Hz, 18H),1.91 (dt, J=13.1, 6.6 Hz, 2H), 1.58 (4 J=14.2, 7.4 Hz, 2H), 1.38-1.29(m, 4H).

Scheme for Hydroxyethylpyrrolidine Linker Synthesis:

Step A: To a 100-mL round-bottom flask was added tert-butyl(3S)-3-aminopyrrolidine-1-carboxylate (2.5 g, 13.42 mmol, 1 equiv),CH₂Cl₂ (20 mL), and sulfonyl chloride INT-L3 (where R¹=m-methyl, 4.72 g,15.90 mmol, 3 equiv). The resulting solution was stirred overnight atroom temperature. The resulting mixture was concentrated under vacuum.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1/100-100/1) providing 3.0 g (50%) oftert-butyl(3S)-3-[[4-(benzyloxy)-3-methylbenzene]sulfonamido]pyrrolidine-1-carboxylate(INT-SE1) as a yellow oil.

Step B: To a 100-mL round-bottom flask was added sulfonamide INT-SE1(3.0 g, 6.72 mmol, 1 equiv), CH₂Cl₂ (15 mL), and trifluoroacetic acid (5mL). The resulting solution was stirred for 1.5 h at room temperature.The pH value of the solution was adjusted to 9-10 with saturated aqueoussodium bicarbonate and extracted with 3×100 mL of ethyl acetate. Theorganic layers were combined and concentrated under vacuum. The residuewas applied onto a silica gel column with CH₂Cl₂/methanol (10:1)providing 2.1 g (90%) of4-(benzyloxy)-3-methyl-N-[(3S)-pyrrolidin-3-yl]benzene-1-sulfonamide(INT-SE2) as an off-white solid.

Step C: To a 100-mL round-bottom flask was added amine INT-SE2 (2.41 g,6.96 mmol, 1 equiv), CH₃CN (20 mL), potassium carbonate (2.5 g, 18.09mmol, 3 equiv), and 1-[2-(2-azidoethoxy)ethoxy]sulfonyl-4-methylbenzene(1.9 g, 6.66 mmol, 1.1 equiv). The resulting slurry was stirredovernight at 60° C. The resulting solution was diluted with water andextracted with 3×100 mL of ethyl acetate. The organic layers werecombined, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:100-100:1) providing 2.4 g(75%) ofN-[(3S)-1-[2-(2-azidoethoxy)ethyl]pyrrolidin-3-yl]-4-(benzyloxy)-3-methylbenzene-1-sulfonamide(INT-SE3) as a yellow oil.

Step D: To a 100-mL round-bottom flask purged and maintained with aninert atmosphere of hydrogen was added azide INT-SE3 (1.0 g, 2.18 mmol,1 equiv), ethyl acetate (5 mL), methanol (5 mL), and 10% palladium oncarbon (500 mg). The resulting slurry was stirred for 2 h at roomtemperature. The solids were filtered out. The residue was applied ontoa silica gel column with CH₂Cl₂/methanol (8:1) providing 420 mg (56%) ofN-[(3S)-1-[2-(2-aminoethoxy)ethyl]pyrrolidin-3-yl]-4-hydroxy-3-methylbenzene-1-sulfonamide(INT-SE4) as an off-white solid.

Step E: To a 25-mL round-bottom flask was added amine INT-SE4 (400 mg,1.16 mmol, 1 equiv), methanol (5 mL), triethylamine (24 mg, 0.24 mmol,0.20 equiv), and ethyl 2,2,2-tri fluoroacetate (653 mg, 4.60 mmol, 4equiv). The resulting solution was stirred for 1.5 h at roomtemperature. The resulting slurry was diluted with water and extractedwith 3×100 mL of ethyl acetate. The organic layers were combined, driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The residue was applied onto a silica gel column with CH₂Cl₂/methanol(10:1) providing 400 mg (78%) of2,2,2-trifluoro-N-(2-[2-[(3S)-3-[(4-hydroxy-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)acetamide(INT-SE5) as a yellow oil.

The R-enantiomer of INT-SE5 was generated from the analogous procedurebeginning with tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate. Thisprovided INT-RES:

Scheme for Hydroxyethylpyrrolidine Dimer Product Synthesis: Example 52:3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimtethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea

Step A: To a 7-mL round-bottom flask was added aminoindanol INT-18C(92.4 mg, 0.38 mmol, 1.1 equiv), tetrahydrofuran (I mL), phenol INT-SE5(150 mg, 0.34 mmol, 1 equiv), and PPh3 (178.9 mg, 0.68 mmol, 2 equiv).Heating at 40° C. in an oil bath DIAD (103.4 mg, 0.51 mmol, 1.5 equiv)was added dropwise with stirring over 15 min. The resulting slurry wasstirred for 1 h at 40-45° C. in an oil bath. The residue was appliedonto a silica gel column with CH₂Cl₂/methanol (10:1) providing 200 mg(88%) ofN-(2-[2-[(3S)-3-[[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-2,2,2-trifluoroacetamide(INT-SE6) as a yellow oil.

Step B: To a 25-mL round-bottom flask was added INT-SE6 (200 mg, 0.30mmol, 1 equiv), methanol (5 mL), and sodium hydroxide (3M_((aq)), 1 mL).The resulting solution was stirred for 1.5 h at 60° C. The resultingsolution was cooled to room temperature and extracted with 3×50 mL ofethyl acetate. The organic layers were combined, dried over anhydroussodium sulfate, filtered, and concentrated under vacuum. The residue wasapplied onto a silica gel column with CH₂Cl₂/methanol (8:1) providing100 mg (58%) ofN-[(3S)-1-[2-(2-aminoethoxy)ethyl]pyrrolidin-3-yl]-4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene-1-sulfonamide(INT-SE7) as a yellow oil.

Step C: To a 25-mL round-bottom flask was added amine INT-SE7 (100 mg,0.17 mmol, 1 equiv), N,N-dimethylformamide (1 mL), and1,4-diisocyanatobutane (0.0945 mL, 0.45 equiv). The resulting solutionwas stirred for 1.5 h at 60° C. The crude product was purified bypreparative HPLC with the following conditions: Column, XBridge ShieldRP18 OBD Column, 19*150 mm, 5 um; mobile phase, water (0.05% TEA) andCH₃CN (24.0% CH₃CN up to 40.0% in 8 min); Detector, UV 220 nm.

Example 52:3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea

Steps A-C provided 42.1 mg (19%) of the title compound as a colorlessviscous oil. MS (m/z): 1283.7 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ7.88-7.82 (m, 2H), 7.79 (s, 2H), 7.56-7.48 (m, 4H), 7.06 (d, J=1.3 Hz,2H), 6.55 (d, J=6.7 Hz, 2H), 4.48 (q, J=8.2 Hz, 2H), 4.09-3.59 (m, 13H),3.54 (t, J=5.3 Hz, 4H), 3.50-3.35 (m, 8H), 3.33 (s, 3H), 3.13 (m, 6H),3.04 (s, 12H), 2.32 (m, 8H), 2.09-1.88 (m, 2H), 1.50 (s, 4H).

Example 53:3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl]carbamoyl]amino]butyl)urea

Beginning with R-enantiomer INT-RES and INT-I8C, Steps A-C provided 19.4mg (21%) of the title compound as a white solid. MS (m/z): 1283.6[M+H]⁺. ¹H NMR (DMSO-d6, 300 MHz) δ 7.68-7.45 (m, 10H), 7.12 (d, J=1.8Hz, 2H), 5.98-5.81 (m, 4H), 5.73 (t, J=5.6 Hz, 2H), 3.54 (s, 2H),3.48-3.21 (m, 10H), 3.16-2.99 (m, 6H), 2.94-2.74 (m, 6H), 2.56 (s, 2H),2.39 (s, 5H), 2.16 (d, J=6.0 Hz, 19H), 1.80 (s, 2H), 1.40 (d, J=7.8 Hz,2H), 1.29-1.15 (m, 8H).

Scheme for Cyano-Containing Hydroxyethylpyrrolidine Dimer ProductSynthesis: Example 54:3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl]carbamoyl]amino]butyl)urea

Step A: To a 8-mL round-bottom flask was added aminoindanol INT-18B(181.84 mg, 0.63 mmol, 1.1 equiv), tetrahydrofuran (I mL), phenolINT-SE5 (250 mg, 0.57 mmol, 1 equiv), and PPh3 (298.1 mg, 1.14 mmol, 2equiv). Heating at 40° C. in an oil bath DIAD (172.4 mg, 0.85 mmol, 1.5equiv) was added dropwise with stirring over 15 min. The resultingsolution was stirred for 1 h at 40-45° C. in an oil bath. The residuewas applied onto a silica gel column with CH₂Cl₂/methanol (10:1)providing 200 mg (49%) ofN-(2-[2-[(3S)-3-[(4-[[(1S,1S)-4-bromo-6-chloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-2,2,2-trifluoroacetamide(INT-SE8) as an off-white solid.

Step B: To a 25-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added bromoaminoindanol INT-SE8 (200mg, 0.28 mmol, 1 equiv), NMP (2 mL), Zn(CN)₂ (19.72 mg, 0.60 equiv), andPd(PPh₃)₄ (32.5 mg, 0.03 mmol, 0.10 equiv). The resulting solution wasstirred overnight at 95° C. The resulting slurry was cooled to roomtemperature, diluted with water, and extracted with 3×50 mL of ethylacetate. The organic layers were combined, dried over anhydrous sodiumsulfate, filtered, and concentrated. The residue was applied onto asilica gel column with CH₂Cl₂/methanol (25:1) providing 150 mg (81%) ofN-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-2,2,2-trifluoroacetamide(INT-SE9) as a yellow oil.

Step C: To a 50-mL round-bottom flask was added INT-SE9 (150 mg, 0.23mmol, 1 equiv), methanol (5 mL), and sodium hydroxide (3M aqueous, 1mL). The resulting solution was stirred for 1.5 h at room temperature.The resulting mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate (100%) providing 60mg (47%) ofN-[(3S)-1-[2-(2-aminoethoxy)ethyl]pyrrolidin-3-yl]-4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene-1-sulfonamide(INT-SE10) as a yellow oil.

Step D: To a 25-mL round-bottom flask was added amine INT-SE10 (60 mg,0.11 mmol, 1 equiv), N,N-dimethylformamide (1 mL), and1,4-diisocyanatobutane (0.00672 mL). The resulting solution was stirredfor 1 h at 60° C. The crude product was purified by preparative HPLCwith the following conditions: Column, XBridge Preparative C18 OBDColumn, 19*150 mm, 5 um; mobile phase, water (0.05% NH₄OH) and CH₃CN(40.0% CH₃CN up to 77.0% in 7 min); Detector, UV 254/220 nm.

Example 54:3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl]carbamoyl]amino]butyl)urea

Steps A-D provided 9.8 mg (7%) of the title compound as a white solid.MS (m/z): 1265.4 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ 7.79-7.74 (m,4H), 7.72-7.68 (m, 2H), 7.48 (d, J=8.7 Hz, 2H), 7.41 (d, J=1.2 Hz, 2H),6.00 (d, J=6.1 Hz, 2H), 4.60 (s, 5H), 3.76 (s, 2H), 3.66-3.49 (m, 6H),3.49-3.39 (m, 5H), 3.37 (d, J=8.0 Hz, 1H), 3.32-3.21 (m, 4H), 3.15-3.03(m, 6H), 2.83-2.74 (m, 2H), 2.63 (t, J=16.1 Hz, 8H), 2.41 (m, 2H), 2.35(s, 12H), 2.26 (s, 6H), 2.11-1.96 (m, 21-), 1.58 (m, 2H), 1.52-1.44 (m,4H).

Example 55:3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamitio]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea

Beginning with R-enantiomer INT-RES and INT-I8B, Steps A-D provided 30.3mg (27%) of the title compound as a white solid. MS (m/z): 1263[M+H]⁺.¹H NMR (DMSO-d6, 400 MHz) δ 8.00 (d, J=1.9 Hz, 2H), 7.69-7.58 (m, 6H),7.57-7.47 (m, 4H), 5.92 (dd, J=29.5, 5.7 Hz, 4H), 5.76 (t, J=5.6 Hz,2H), 3.58-3.45 (m, 5H), 3.38 (t, J=6.2 Hz, 4H), 3.31-3.18 (m, 8H),3.12-2.87 (m, 13H), 2.59 (s, 2H), 2.42 (s, 5H), 2.18 (d, J=10.9 Hz,18H), 1.83 (t, J=10.5 Hz, 2H), 1.43 (s, 2H), 1.32-1.19 (m, 5H).

Scheme for Synthesis of Triazole-Type Linker Compounds

Step A: To a 250-mL round-bottom flask was added2-[2-(2-aminoethoxy)ethoxy]ethan-1-ol (5.3 g, 35.53 mmol, 2 equiv),CH₂Cl₂ (50 mL), triethylamine (5.37 g, 53.07 mmol, 3 equiv), and INT-L3(R¹═H, 5 g, 17.7 mmol, 1 equiv). The resulting solution was stirredovernight. The reaction was then quenched by the addition of 50 mL ofwater and extracted with 3×50 mL of ethyl acetate. The organic layerswere combined, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with CH₂Cl₂/methanol (0-55%) providing 6.4 g (92%) of2-[2-(2-[[4-(benzyloxy)benzene]sulfonamido]ethoxy)ethoxy]ethan-1-ol(INT-T1) as a white solid.

Step B: To a 250-mL round-bottom flask was added INT-T1 (6.4 g, 16.2mmol, 1 equiv), CH₂Cl₂ (50 mL), triethylamine (3.3 g, 32.6 mmol, 2equiv), and p-TsCl (4.6 g, 24.13 mmol, 1.5 equiv). The resultingsolution was stirred overnight. The reaction was quenched by theaddition of 50 mL of water and extracted with 3×50 mL of CH₂Cl₂. Theorganic layers were combined, dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was applied onto asilica gel column with petroleum ether/ethyl acetate (0-50%) providing8.3 g (93%) of2-[2-(2-[[4-(benzyloxy)benzene]sulfonamido]ethoxy)ethoxy]ethyl4-methylbenzene-1-sulfonate (INT-T2) as a white solid.

Step C: To a 250-mL round-bottom flask was added INT-T2 (8.3 g, 15.1mmol, 1 equiv), N,N-dimethylformamide (20 mL), and NaN₃ (1.47 g, 22.6mmol, 1.5 equiv). The resulting slurry was stirred for 5 h at 90° C. Thereaction was then quenched by the addition of 50 mL of water andextracted with 3×50 mL of ethyl acetate. The organic layers werecombined, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with petroleum ether/ethyl acetate (0-50%) providing 6 g (94%) of2-[12-(2-azidoethoxy)ethoxy]-S-[4-(benzyloxy)phenyl]ethane-1-sulfonamido(INT-T3) as a white solid.

Step D: To a 100-mL round-bottom flask was added INT-T3 (6.6 g, 15.70mmol, 1 equiv) and CH₂Cl₂ (20 mL), followed by the addition of BBr₃(11.8 g, 47.1 mmol 3 equiv) dropwise with stirring at −60° C. Theresulting solution was stirred for 30 min at −60° C. The reaction wasthen carefully quenched by the addition of 50 mL of watertice. Theresulting solution was extracted with 3×50 mL of ethyl acetate. Theorganic layers were combined, dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was applied onto asilica gel column with petroleum ether/ethyl acetate (0-50%) providing 5g (crude) of2-[2-(2-azidoethoxy)ethoxy]-S-(4-hydroxyphenyl)ethane-1-sulfonamido(INT-T4) as a yellow oil.

Step E: To a 7-mL round-bottom flask was added INT-T4 (100 mg, 0.30mmol, 1 equiv), NA-dimethylformamide (2 mL),2,2,2-trifluoro-N-(prop-2-yn-1-yl)acetamide (55 mg, 0.36 mmol, 1.2equiv), sodium ascorbate (11.97 mg), and CuSO₄.5H₂O (7.54 mg). Theresulting slurry was stirred for 3 h at room temperature. The resultingsolution was diluted with 20 mL of ethyl acetate and quenched by theaddition of 20 mL of water. The resulting solution was extracted with3×20 mL of ethyl acetate. The organic layers were combined, washed with3×50 mL of brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with petroleum ether/ethyl acetate (100%) providing 80 mg (55%)of2,2,2-trifluoro-N-([1-[2-(2-[2-[(4-hydroxybenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)acetamide(INT-T5) as a colorless oil.

Step F: To a 25-mL round-bottom flask was added aminoindanol INT-18E(693 mg, 1.73 mmol, 1 equiv), phenol INT-T5 (1.0 g, 2.08 mmol, 1.2equiv), PPh3 (682 mg, 2.60 mmol, 1.51 equiv), and THE (4 mL). Heating at40° C. in an oil bath DIAD (526 mg, 2.60 mmol, 1.51 equiv) was added inportions over 20 min. The resulting solution was stirred for 1 h at 40°C. in an oil bath. The resulting slurry was concentrated under vacuum.The residue was applied onto a silica gel column with petroleumether/ethyl acetate (100%) providing 2.0 g (crude) of tert-butylN-[(3R)-1-[(1S,2S)-4,6-dichloro-1-[4-([2-[2-(2-[4-[(trifluoroacetamido)methyl]-1H-1,2,3-triazol-1-yl]ethoxy)ethoxy]ethyl]sulfamoyl)phenoxy]-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-T6) as a yellow oil.

Step G: To a 100-mL round-bottom flask was added INT-T6 (2.0 g, 2.31mmol, 1 equiv), methanol (25 mL), and sodium hydroxide (3M (aq), 3 mL).The resulting slurry was stirred for 2 h at 60° C. in an oil bath. Theresulting mixture was concentrated under vacuum. The resulting solutionwas extracted with 3×100 ml, of ethyl acetate. The organic layers werecombined, washed with 1×100 mL of brine, dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue wasapplied onto a silica gel column with CH₂Cl₂/methanol (10:1) providing1.06 g (60%) of tert-butylN-[(3R)-1-[(1S,2S)-1-(4-[[2-(2-[2-[4-(aminomethyl)-1H-1,2,3-triazol-1-yl]ethoxy]ethoxy)ethyl]sulfamoyl]phenoxy)-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamateas an off-white solid.

Scheme for the Synthesis of Triazole-Type Dimer Products: Example 56:1-([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-3-(4-[[([(1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)carbamoyl]amino]butyl)urea

Step A: To a 7-mL round-bottom flask was added amine INT-T7 (400 mg,0.52 mmol, 1 equiv), DMF (3 mL), and 1,4-diisocyanatobutane (29 mg, 0.21mmol, 0.4 equiv). The resulting solution was stirred for 2 h at 60° C.in an oil bath. The resulting solution was diluted with 50 mL of water.The resulting solution was extracted with 3×50 mL of ethyl acetate. Theorganic layers were combined, washed with 3×50 mL of brine, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was applied onto a silica gel column with CH₂Cl₂/methanol (10:1)providing 320 mg (37%) of tert-butylN-[(3R)-1-[(1S,2S)-1-(4-[[2-(2-[2-[4-([[(4-[[(1-([2-(2-[2-([4-[[(1S,2S)-2-[(3R)-3-[[(tert-butoxy)carbonyl]amino]piperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)carbamoyl]amino]butyl)carbamoyl]amino]methyl)-1H-1,2,3-triazol-1-yl]ethoxy]ethoxy)ethyl]sulfamoyl]phenoxy)-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-T8) as a brown solid.

Step B: To a 25-mL round-bottom flask was added INT-T8 (320 mg, 0.19mmol, 1 equiv) and 20% TFA in CH₂Cl₂ (10 mL). The resulting solution wasstirred for 1 h at room temperature. The resulting solution was dilutedwith 20 mL of CH₂Cl₂. The pH value of the solution was adjusted to 9-10with saturated sodium bicarbonate and extracted with 3×100 mL of ethylacetate. The organic layers were combined, washed with 1×100 mL ofbrine, dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum. The crude product was purified by preparative HPLC withthe following conditions: Column, XBridge C18 OBD Preparative Column,19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN (28.0% CH₃CNup to 52.0% in 8 min); Detector, UV 254 nm.

Example 56:1-([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-3-(4-[[(1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)carbamoyl]amino]butyl)urea

Steps A and B provided 137.6 mg (49%) of the title compound as anoff-white solid. MS (m/z): 1477 [M+H]⁺. ¹H NMR (Methanol-d4, 300 MHz) δ7.90-7.79 (m, 6H), 7.44 (d, J=1.7 Hz, 2H), 7.31-7.21 (m, 4H), 7.11-7.04(m, 2H), 6.31 (d, J=6.0 Hz, 2H), 4.51 (t, J=4.9 Hz, 4H), 4.31 (s, 4H),4.03 (d, 6.8 Hz, 2H), 3.83 (t, J=5.0 Hz, 4H), 3.59-3.36 (m, 18H),3.22-2.98 (m, 12H), 2.87 (dt, J=20.0, 10.8 Hz, 4H), 2.00 (s, 2H), 1.83(s, 1H), 1.63 (d, J=10.2 Hz, 2H), 1.43 (s, 4H).

Scheme for Synthesis of Protected Galactaric Acid

Step A: To a 1-L round-bottom flask was added(2R,3S,4R,5S)-2,3,4,5-tetrahydroxyhexanedioic acid (galactaric acid, 20g, 95.2 mmol, 1 equiv), methanol (386 mL), and sulfuric acid (5.08 mL, 1equiv). The resulting solution was stirred for 96 h at 70° C. Theresulting solution was allowed to react, with stirring, for anadditional 36 h at room temperature. The solids were collected byfiltration. The resulting mixture was concentrated under vacuum. Thisresulted in 20.3 g (90%) of 1,6-dimethyl(2R,3S,4R,5S)-2,3,4,5-tetrahydroxyhexanedioate as a white solid.

Step B: To a 250-mL round-bottom flask was added 1,6-dimethyl(2R,3S,4R,5S)-2,3,4,5-tetrahydroxy hexanedioate (5.0 g, 21 mmol, 1equiv), 2,2-dimethoxypropane (26 mL, 0.01 equiv), acetone (50 mL), and[(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl]methanesulfonicacid (camphorsulfonic acid, 1.105 g, 4.76 mmol, 0.2 equiv). The mixturewas stirred for 1 h at 65° C. The reaction was then quenched by theaddition of K₂CO₃ (3M_((aq))) and concentrated under vacuum. Theresulting slurry was extracted with 3×100 mL of CH₂Cl₂. The organiclayers were combined, washed with 1×100 mL of brine, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Thecrude product was purified by re-crystallization from methanol. Thesolids were collected by filtration providing 2.9 g (43%) of methyl (4R,5S)-5-[(4R,5S)-5-(methoxycarbonyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-1,3-dioxolane-4-carboxylateas a white solid.

Step C: To a 100-mL round-bottom flask was added methyl(4R,5S)-5-[(4R,5S)-5-(methoxycarbonyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-1,3-dioxolane-4-carboxylate(2.5 g, 7.85 mmol, 1 equiv), water (30 mg), and sodium hydroxide (785mg, 19.63 mmol, 5 equiv). The resulting solution was stirred overnightat 60° C. The reaction was then quenched by the addition of 50 mL ofhydrogen chloride (1M_((aq)) in ice. The resulting solution wasextracted with 3×100 ml, of ethyl acetate. The organic layers werecombined, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum providing 2.0 g (80%) of(4R,4′S,5S,5′R)-2,2,2′,2′-tetramethyl-[4,4′-bi(1,3-dioxolane)]-5,5′-dicarboxylicacid as a white solid.

Scheme for Synthesis of Triazole-Type Dimer Products with GalactaricAcid Core:

Example 57:(2R,3S,4R,5S)—N¹,N⁶-Bis([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-2,3,4,5-tetrahydroxyhexanediamide

Step A: To a 25-mL round-bottom flask was added amine INT-T7 (300 mg,0.39 mmol, 2.2 equiv),(4R,5S)-5-[(4R,5S)-5-carboxy-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-1,3-dioxolane-4-carboxylicacid (51.54 mg, 0.18 mmol, 1 equiv), DMF (8 mL), diisopropylethylamine(115 mg, 0.89 mmol, 5 equiv), and HATU (202.92 mg, 0.53 mmol, 3 equiv).The resulting solution was stirred for 2 h at room temperature. Thereaction was quenched by the addition of 20 mL of water and theresulting solution was extracted with 3×50 mL of ethyl acetate. Theorganic layers were combined, washed with 3×100 mL of brine, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was applied onto a silica gel column with CH₂Cl₂/methanol (10:1)providing 340 mg (crude) of INT-T9 as a white solid.

Step B: To a 25-mL round-bottom flask was added INT-T9 (450 mg, 0.25mmol, 1 equiv) and TFA/H₂O (7/0.35 mL). The resulting solution wasstirred for 3 h at room temperature. The resulting mixture wasconcentrated under vacuum. The crude product was purified by preparativeHPLC with the following conditions: Column, XBridge C18 OBD PreparativeColumn, 19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN(28.0% CH₃CN up to 45.0% in 12 min); Detector, UV 254 nm.

Example 57:(2R,3S,4R,5S)—N¹,N⁶-Bis([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-2,3,4,5-tetrahydroxyhexanediamide

Steps A and B provided 72.3 mg (19%) of the title compound as a whitesolid. MS (m/z): 1511 [M+H]⁺. ¹H NMR (Methanol-d4, 300 MHz) δ 7.94-7.79(m, 6H), 7.42 (s, 2H), 7.26 (d, J=8.6 Hz, 4H), 7.08 (s, 2H), 6.21 (t,J=6.3 Hz, 2H), 4.56-4.44 (m, 8H), 4.39 (d, J=1.1 Hz, 2H), 4.00 (s, 2H),3.93-3.78 (m, 6H), 3.59-3.27 (m, 17H), 3.03 (t, J=5.4 Hz, 10H),2.85-2.71 (m, 4H), 1.92 (d, J=18.5 Hz, 3H), 1.76 (s, 2H), 1.59 (d J=9.8Hz, 2H).

Scheme for Synthesis of Aliphatic Triazole-Type Intermediates:

Step A: To a 250-mL round-bottom flask, was added aminoindanol INT-18F(2.0 g, 5 mmol, 1 equiv), 4-bromophenol (1.3 g, 7.5 mmol, 1.5 equiv),PPh3 (2.62 g, 10 mmol, 2 equiv), and tetrahydrofuran (100 mL). Heatingat 40° C. in an oil bath DIAD (2.02 g, 10 mmol, 1.5 equiv) was addeddropwise with stirring over 20 min. The resulting solution was stirredfor 3 h at 40° C. The resulting mixture was concentrated under vacuum.The residue was applied onto a silica gel column with petroleumether/ethyl acetate (10:1-8:1) providing 2.5 g (90%) of tert-butylN-[(3R)-1-[(1S,2S)-1-(4-bromophenoxy)-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-T10) as a light yellow solid.

Step B: To a 250-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added bromide INT-T10 (2.5 g, 4.14mmol, 1 equiv), 1,4-dioxane (100 mL), benzyl mercaptan (1.12 g, 9 mmol,2 equiv), Xantphos (260 mg, 0.45 mmol, 0.10 equiv), anddiisopropylethylamine (1.46 g, 11.3 mmol, 2.73 equiv). This was followedby the addition of Pd₂(dba)₃.CHCl₃ (240 mg, 0.23 mmol, 0.05 equiv) inportions at room temperature. The resulting solution was stirred for 14h at 100° C. The resulting mixture was concentrated under vacuum and theresidue was dissolved in 150 mL of ethyl acetate. The resulting mixturewas washed with 3×80 mL of water and 1×80 mL of saturated aqueous sodiumchloride. The organic layers were combined, dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue wasapplied onto a silica gel column with petroleum ether/ethyl acetate(10:1-3:1) providing 2.5 g (93%) of tert-butylN-[(3R)-1-[(1S,2S)-1-[4-(benzylsulfanyl)phenoxy]-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-T11) as a brown solid.

Step C: To a 100-mL round-bottom flask was added thioether INT-T11 (2.5g, 4.17 mmol, 1 equiv), acetic acid (24 mL), and water (8 mL). This wasfollowed by the addition of NCS (1.93 g, 14.45 mmol, 3.5 equiv) inportions at 0° C. The resulting solution was stirred for 4 h at roomtemperature. The resulting slurry was diluted with 30 mL of water. ThepH value of the solution adjusted to 8 with saturated aqueous sodiumbicarbonate and extracted with 3×80 mL of ethyl acetate. The organiclayers were combined and washed with 1×100 mL of water and 1×100 mL ofbrine. The mixture was dried over anhydrous sodium sulfate, filtered,and concentrated under vacuum. This resulted in 2.0 g (83%) of crudetert-butylN-[(3R)-1-[(1S,2S)-4,6-dichloro-1-[14-(chlorosulfonyl)phenoxy]-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamateas a brown solid.

Step D: To a 250-mL round-bottom flask was added sulfonyl chlorideINT-T12 (2.0 g, 3.47 mmol, 1 equiv), CH₂Cl₂ (50 mL), triethylamine (1.4mL, 3 equiv), and 4-aminobutan-1-ol (0.64 mL, 2 equiv). The resultingsolution was stirred overnight at room temperature. The resulting slurrywas diluted with water and extracted with 3×150 mL of CH₂Cl₂. Theorganic layers were combined and washed with 1×100 mL of water and 1×100mL of brine. The mixture was dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was applied onto asilica gel column with petroleum ether/ethyl acetate (1:2) providing1.47 g (67%) of tart-butylN-[(3R)-1-[(1S,2S)-4,6-dichloro-1-[4-[(4-hydroxybutyl)sulfamoyl]phenoxy]-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-T13) as a yellow oil.

Step E: To a 250-mL round-bottom flask was added alcohol INT-T13 (1.47g, 2.34 mmol, 1 equiv), CH₂Cl₂ (30 mL), triethylamine (1.3 mL, 4 equiv),and p-toluenesulfonyl chloride (1.34 g, 7.03 mmol, 3 equiv). Theresulting solution was stirred overnight at room temperature. Theresulting slurry was diluted with water and extracted with 3×150 mL ofCH₂Cl₂. The organic layers were combined and washed with 1×100 mL ofwater and 1×100 mL of brine. The mixture was dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue wasapplied onto a silica gel column with petroleum ether/ethyl acetate(1:1) providing 1.46 g (80%) of tert-butylN-[(3R)-1-[(1S,2S)-4,6-dichloro-1-[4-[(4-[[(4-methylbenzene)sulfonyl]oxy]butyl)sulfamoyl]phenoxy]-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-T14) as a yellow solid.

Step F: To a 100-mL round-bottom flask was added tosylate INT-T14 (1.46g, 1.87 mmol, 1 equiv), DMF (10 mL), and sodium azide (182 mg, 2.80mmol, 1.5 equiv). The resulting solution was stirred overnight at 90° C.The resulting slurry was diluted with water and extracted with 3×150 mLof ethyl acetate. The organic layers were combined and washed with 1×100mL of water and 1×100 mL of brine. The mixture was dried over anhydroussodium sulfate, filtered, and concentrated under vacuum. The residue wasapplied onto a silica gel column with petroleum ether/ethyl acetate(1:1) providing 1.06 g (87%) of tert-butylN-[(3R)-1-[(1S,2S)-1-[4-[(4-azidobutyl)sulfamoyl]phenoxy]-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl](carbamate(INT-T15) as a yellow oil.

Step G: To a 50-mL round-bottom flask was azide INT-T15 (500 mg, 0.76mmol, 1 equiv), 2,2,2-trifluoro-N-(prop-2-yn-1-yl)acetamide (280 mg,1.85 mmol, 2.4 equiv), 2-methylpropan-2-ol (12 mL), water (5 mL), sodiumascorbate (30 mg, 0.15 mmol, 0.2 equiv), and CuSO₄.5H₂O (20 mg, 0.08mmol, 0.1 equiv). The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Theresulting solution was diluted with water and extracted with 3×100 mL ofCH₂Cl₂. The organic layers were combined and washed with 1×100 mL ofwater and 1×100 mL of brine. The mixture was dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue wasapplied onto a silica gel column with petroleum ether/ethyl acetate(1:1) providing 480 mg (78%) of tert-butylN-[(3R)-[[(1S,2S)-4,6-dichloro-1-[4-[(4-[4-1(trifluoroacetamido)methyl]-1H-1,2,3-triazol-1-yl]butyl)sulfamoyl]phenoxy]-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-T16) as a white solid.

Step H: To a 100-mL round-bottom flask was added INT-T16 (432 mg, 0.54mmol, 1 equiv), methanol (20 mL), and sodium hydroxide (3M_((aq)), 0.4mL). The resulting solution was stirred for 1 h at 60° C. The resultingsolution was extracted with 3×100 mL of CH₂Cl₂. The organic layers werecombined and washed with 1×50 mL of water and 1×50 mL of brine. Themixture was dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with CH₂Cl₂/methanol (10:1) providing 356 mg (94%) of tert-butylN-[(3R)-1-[(1S,2S)-1-[4-([4-[4-(aminomethyl)-1H-1,2,3-triazol-1-yl]butyl]sulfamoyl)phenoxy]-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-T17) as a white solid.

The 6-carbon intermediate was generated from the analogous procedurebeginning with 6-aminohexan-1-ol. This provided INT-T18:

General Scheme for Aliphatic Triazole-Type Dimer Products: Example 58:3-[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)methyl]-1-[4-([[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)methyl]carbamoyl]amino)butyl]urea

Step A: To a 50-mL round-bottom flask was added amine INT-T17 (394 mg,0.56 mmol, 1 equiv), DMF (4.7 mL), and 1,4-diisocyanatobutane (39 mg,0.28 mmol, 0.5 equiv). The resulting solution was stirred for 1 h at 60°C. The resulting mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column with CH₂Cl₂/methanol (10:1) providing455 mg (crude) of tert-butylN-[(3R)-1-[(1S,2S)-1-[4-[(4-[4-[([[4-([[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-[[(tert-butoxy)carbonyl]amino]piperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)methyl]carbamoyl]amino)butyl]carbamoyl]amino)methyl]-1H-1,2,3-triazol-1-yl]butyl)sulfamoyl]phenoxy]-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-T19) as a yellow oil.

Step B: To a 50-mL round-bottom flask was added dimer INT-T19 (455 mg,0.29 mmol, 1 equiv), CH₂Cl₂ (10 mL), and trifluoroacetic acid (1.5 mL).The resulting solution was stirred for 1 h at room temperature. The pHvalue of the solution was adjusted to 8 with saturated aqueous potassiumcarbonate and extracted with 3×150 mL of CH₂Cl₂. The organic layers werecombined and washed with 1×100 mL of water and 1×100 mL of brine. Themixture was dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The crude product was purified bypreparative-HPLC with the following conditions: Column, XBridge C18 OBDPreparative Column, 19*250 mm, 5 um; mobile phase, water (10 mmol/LNH₄HCO₃) and CH₃CN (50.0% CH₃CN up to 65.0% in 8 min); Detector, UV 254nm.

Example 58:3-[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)methyl]-1-[4-([[1-([4-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)methyl]carbamoyl]amino)butyl]urea

Steps A and B provided 94 mg (24%) of the title compound as a whitesolid. MS (m/z): 1357.05 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ 7.80(t, J=3.6 Hz, 6H), 7.40-7.15 (m, 8H), 5.95 (d, J=5.2 Hz, 2H), 4.35 (t,7.0 Hz, 8H), 3.59 (q, J=6.6 Hz, 2H), 3.22-3.10 (m, 6H), 3.04-2.92 (m,2H), 2.85 (q, J=6.6 Hz, 8H), 2.72 (d, J=11.2 Hz, 2H), 2.25 (t, J=8.0 Hz,2H), 2.15 (t, J=8.4 Hz, 2H), 1.95-1.79 (m, 6H), 1.79-1.70 (m, 2H),1.60-1.50 (m, 2H), 1.49-1.40 (m, 8H), 1.29 (d, J=18.4 Hz, 3H), 1.18 (q,J=5.4 Hz, 2H).

Example 59:3-[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamino]hexyl]-1H-1,2,3-triazol-4-yl)methyl]-1-[4-([[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]hexyl]-1H-1,2,3-triazol-4-yl)methyl]carbamoyl]amino)butyl]urea.Beginning with INT-T18

Steps A and B provided 221 mg (55%) of the title compound as a whitesolid. MS (m/z): 1413 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ 7.96-7.87(m, 6H), 7.54 (d, J=1.7 Hz, 2H), 7.45-7.37 (m, 4H), 7.08-7.02 (m, 2H),6.74 (d, 1=6.5 Hz, 2H), 4.52-4.36 (m, 10H), 3.79 (s, 2H), 3.70 (q, J=7.8Hz, 6H), 3.42 (dd, J=16.3, 8.4 Hz, 2H), 3.30-3.09 (m, 8H), 2.89 (t,J=6.8 Hz, 4H), 2.18 (d, J=15.1 Hz, 4H), 2.08 (d, J=14.3 lit, 2H), 1.88(p, J=7.2 Hz, 4H), 1.81-1.68 (m, 2H), 1.57-1.42 (m, 8H), 1.39-1.19 (m,10H).

General Scheme for Synthesis of Aliphatic Triazole-Type Dimer Productswith Galactaric Acid Core:

Step A: To a 25-mL round-bottom flask was added amine INT-T17 (300 mg,0.42 mmol, 2.2 equiv),(4R,5S)-5-[(4R,5S)-5-carboxy-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-1,3-dioxolane-4-carboxylicacid (55.9 mg, 0.19 mmol, 1 equiv), DMF (8 mL), diisopropylethylamine(124.5 mg, 0.96 mmol, 5 equiv), and HATU (220.02 mg, 0.58 mmol, 3equiv). The resulting solution was stirred for 2 h at room temperature.The reaction was quenched by the addition of 20 mL of water andextracted with 3×50 mL of ethyl acetate. The organic layers werecombined, washed with 3×100 mL of brine, dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue wasapplied onto a silica gel column with CH₂Cl₂/methanol (10:1) providing350 mg (crude) of tert-butylN-[(3R)-1-[(1S,2S)-1-[4-([4-[4-([[(4S,4aR,8R,8aS)-8-[[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-[[(tert-butoxy)carbonyl]amino]piperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)methyl]carbamoyl]-2,2,6,6-tetramethyl-hexahydro-[1,3]dioxino[5,4-d][1,3]dioxin-4-yl]formamido]methyl)-1H-1,2,3-triazol-1-yl]butyl]sulfamoyl)phenoxy]-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-T20) as a white solid.

Step B: To a 25-mL round-bottom flask was added dimer INT-T20 (480 mg,0.29 mmol, 1 equiv), and TFA/H₂O (7/0.35 mL). The resulting solution wasstirred for 3 h at room temperature. The resulting mixture wasconcentrated under vacuum. The crude product was purified by preparativeHPLC with the following conditions: Column, XBridge C18 OBD PreparativeColumn, 19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN(28.0% CH₃CN up to 43.0% in 8 min); Detector, UV 254 nm.

Example 60:(4R,4aS,8S,8aR)—N⁴,N⁸-Bis([1-(4-[4-((1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenylsulfonamide]butyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-tetrahydro-[1,3]dioxino[5,4-d][1,3]dioxine-4,8-dicarboxamide

Steps A and B provided 190.0 mg (48%) of the title compound as a whitesolid. MS (m/z): 1389 [M+H]⁺. ¹H NMR (Methanol-d4, 300 MHz) δ 7.85-7.76(m, 6H), 7.45-7.38 (m, 2H), 7.27 (d, J=8.7 Hz, 4H), 7.13-7.06 (m, 2H),6.13 (d, J=5.7 Hz, 2H), 4.61-4.26 (m, 10H), 4.00 (s, 2H), 3.82 (s, 2H),3.37 (d, J=18.5 Hz, 4H), 3.03 (dd, J=16.6, 7.7 Hz, 4H), 2.86 (dt, J=7.2,3.6 Hz, 6H), 2.68 (s, 4H), 1.88 (dd, J=14.5, 7.1 Hz, 8H), 1.72 (s, 2H),1.57 (d, J=10.9 Hz, 2H), 1.40 (t, J=7.5 Hz, 4H).

Example 61: (4R,4aS,8S,8aR)—N⁴,N⁸-Bis([1-(6-[4-((1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenylsulfonamido]hexyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-tetrahydro-[1,3]dioxino[5,4-d][1,3]dioxine-4,8-dicarboxamide

Beginning with INT-T18, Steps A and B provided 130.8 mg (52%) of thetitle compound as a white solid. MS (m/z): 1445 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.84 (dd, J=6.9, 1.9 Hz, 6H), 7.44 (d, J=1.8Hz, 2H), 7.34-7.26 (m, 4H), 7.15-7.09 (m, 2H), 6.08 (d, J=5.5 Hz, 2H),4.61-4.39 (m, 5H), 4.34 (t, J=7.0 Hz, 4H), 4.02 (s, 2H), 3.74 (q, J=7.1Hz, 2H), 3.42-3.35 (m, 2H), 3.31-3.22 (m, 2H), 3.08-2.93 (m, 4H), 2.85(t, J=6.8 Hz, 4H), 2.76 (s, 2H), 2.70-2.60 (m, 4H), 1.87 (tt, J=14.4,8.2 Hz, 8H), 1.69 (s, 2H), 1.58 (s, 2H), 1.48-1.20 (m, 13H).

General Scheme for Synthesis of Alkyl Linker Monomers:

Step A: To a 250-mL round-bottom flask, was added tert-butylN-(8-aminooctyl)carbamate (2 g, 8.18 mmol, 1.1 equiv), CH₂Cl₂ (30 mL),and triethylamine (3 mL, 3 equiv). This was followed by the addition of4-(benzyloxy)benzene-1-sulfonyl chloride (INT-L3 where R¹═H, 2.1 g, 7.43mmol, 1 equiv) in several portions. The resulting solution was stirredovernight at room temperature. The resulting solution was diluted withwater and extracted with 3×100 mL of CH₂Cl₂. The organic layers werecombined and washed with 2×150 mL of brine. The mixture was dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was applied onto a silica gel column with petroleum ether/ethylacetate (2:1) providing 3.3 g (91%) of tert-butylN-(8-[[4-(benzyloxy)benzene]sulfonamido]octyl)carbamate (INT-C1) as awhite solid.

Step B: To a 250-mL round-bottom flask was added sulfonamide INT-C1 (2.7g, 5.50 mmol, 1 equiv), CH₂Cl₂ (30 mL), and trifluoroacetic acid (4 mL).The resulting solution was stirred for 1 h at room temperature. The pHvalue of the solution was adjusted to 9 with saturated aqueous NaHCO₃.The solids were collected by filtration. This resulted in 1.8 g (84%) ofN-(8-aminooctyl)-4-(benzyloxy)benzene-1-sulfonamide (INT-C2) as a whitesolid.

Step C: To a 250-mL round-bottom flask was added amine INT-C2 (1.68 g,4.30 mmol, 1 equiv), methanol (20 mL), and triethylamine (2.3 mL, 4equiv). This was followed by the addition of ethyl trifluoroacetate (1.2mL, 2 equiv) dropwise with stirring at room temperature. The resultingsolution was stirred for 1 h at room temperature. The resulting solutionwas diluted with water and extracted with 100 mL of ethyl acetate. Theorganic layers were combined and washed with 2×150 mL of brine. Themixture was dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with petroleum ether/ethyl acetate (2:1) providing 2 g (96%) ofN-(8-[[4-(benzyloxy)benzene]sulfonamido]octyl)-2,2,2-trifluoroacetamide(INT-C3) as a white solid.

Step D: To a 250-mL round-bottom flask was added benzyl ether INT-C3 (2g, 4.11 mmol, 1 equiv), methanol (20 mL), and 10% palladium on carbon (1g). To the above H_(2(g)) was introduced in and the resulting slurry wasstirred for 1 h at room temperature. The solids were filtered out andthe resulting mixture concentrated under vacuum. The residue was appliedonto a silica gel column with petroleum ether/ethyl acetate (1:1)providing 1.6 g (98%) of2,2,2-trifluoro-N-[8-[(4-hydroxybenzene)sulfonamido]octyl]acetamide(INT-C4) as a white solid.

Step E: To a 50-mL round-bottom flask was added phenol INT-C4 (1.6 g,4.04 mmol, 1 equiv), THF (18 mL), and aminoindanol INT-18F (1.78 g, 4.44mmol, 1.1 equiv). This was followed by the addition of PPh3 (1.79 g,6.82 mmol, 1.7 equiv) in several batches with heating at 40° C. To thiswas added DIAD (1.27 mL, 1.6 equiv) dropwise with stirring at 40° C.over 30 min. The resulting solution was stirred for 1 h at 40° C. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with petroleum ether/ethyl acetate (2:1)providing 2.8 g (89%) of tert-butyl(3R)-1-((1S,2S)-4,6-dichloro-1-(4-(N-(8-(2,2,2-trifluoroacetamido)octyl)sulfamoyl)phenoxy)-2,3-dihydro-1H-inden-2-yl)piperidin-3-ylcarbamate(INT-C5) as a yellow solid.

Step F: To a 250-mL round-bottom flask was added INT-C5 (2.8 g, 3.59mmol, 1 equiv), methanol (30 mL), and sodium hydroxide (3M_((aq)), 4mL). The resulting solution was stirred for 1 h at 60° C. The resultingsolution was extracted with 3×100 mL of ethyl acetate. The organiclayers combined and washed with 2×150 mL of brine. The mixture was driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The residue was applied onto a silica gel column with CH₂Cl₂/methanol(5:1) providing 2.2 g (90%) of tert-butylN-[(3R)-1-[(1S,2S)-1-[4-[(8-aminooctyl)sulfamoyl]phenoxy]-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-C6) as a yellow solid.

The following intermediates are made by applying the above procedures tothe appropriate starting aminoindanols INT-I8 and sulfonyl chloridesINT-L3:

General Scheme for Synthesis of Alkyl Linker Dimer Products: Example 62:3-[8-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea; bis(trifluoroacetic acid)

Step A: To a 0.50-mL round-bottom flask, was added amine INT-C6 (300 mg,0.44 mmol, 1 equiv), DMF (3 mL), and 1,4-diisocyanatobutane (25 mL, 0.45equiv). The resulting solution was stirred for 1 h at 60° C. Theresulting mixture was concentrated under vacuum. The resulting solutionwas diluted with 2 mL of CH₂Cl₂. The residue was applied onto a silicagel column with CH₂Cl₂/methanol (8:1) providing 260 mg (39%) oftext-butylN-[(3R)-1-[(1S,2S)-1-[4-([8-[([4-[([8-[4-[[(1S,2S)-2-[(3R)-3-[[(tert-butoxy)carbonyl]amino]piperidin-1-yl]-4,6dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]carbamoyl)amino]butyl]carbamoyl)amino]octyl]sulfamoyl)phenoxy]-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-C10) as a yellow solid.

Step B: To a 25-mL round-bottom flask was added dimer INT-C10 (260 mg,0.17 mmol, 1 equiv), CH₂Cl₂ (8 mL), and trifluoroacetic acid (1.5 mL).The resulting solution was stirred for 1 h at room temperature. Theresulting mixture was concentrated under vacuum and diluted with 4 mL ofmethanol. The solids were filtered out. The crude product was purifiedby preparative HPLC with the following conditions: Column, XBridge C18OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water (0.05% TFA)and CH₃CN (18.0% CH₃CN up to 32.0% in 8 min); Detector, UV 254 nm.

Example 62:3-[8-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea; bis(trifluoroacetic acid)

Steps A and B provided 136.5 mg (52%) of the title compound as a whitesolid. MS (m/z): 1307 [M+H]⁺ NMR (Methanol-d4, 400 MHz) δ 7.92-7.83 (m,4H), 7.46 (d, J=1.8 Hz, 2H), 7.37-7.28 (m, 4H), 7.17 (dd, J=1.9, 0.8 Hz,2H), 6.08 (d, J=5.5 Hz, 2H), 3.75 (dt, J=13.6, 7.4 Hz, 2H), 3.39 (dt,J=9.8, 5.0 Hz, 4H), 3.33-3.24 (m, 2H), 3.16-2.93 (m, 13H), 2.88 (t,J=7.0 Hz, 4H), 2.77 (s, 2H), 2.71-2.61 (m, 5H), 1.92 (s, 4H), 1.71 (s,2H), 1.61 (d, J=8.8 Hz, 3H), 1.48 (dp, J=11.6, 4.4, 3.8 Hz, 12H),1.33-1.27 (m, 16H).

Example 63:3-[8-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea

Beginning with INT-C7 and INT-18F, Steps A and B provided 73.6 mg (24%)of the title compound as a pink solid. MS (m/z): 1335.95 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.87-7.74 (m, 4H), 7.63-7.52 (m, 4H), 7.02 (s,2H), 6.87 (d, J=6.2 Hz, 2H), 4.61 (d, J=7.6 Hz, 2H), 3.92-3.70 (m, 7H),3.49 (dd, J=24.0, 11.8 Hz, 2H), 3.35 (s, 4H), 3.19-3.06 (m, 8H), 2.90(t, J=6.8 Hz, 4H), 2.33 (s, 6H), 2.30-2.05 (m, 6H), 1.79 (d, J=12.8 Hz,2H), 1.55-1.44 (m, 12H), 1.30 (s, 16H).

Example 64:3-[8-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea; bis(trifluoroacetic acid)

Beginning with INT-C8 and INT-18C, Step A provided 185 mg (48%) of thetitle compound as a white solid. MS (m/z): 1197 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.95-7.87 (m, 4H), 7.57-7.51 (m, 2H), 7.41-7.32(m, 4H), 7.11 (d, 1.3 Hz, 2H), 6.44 (d, J=6.8 Hz, 2H), 4.44 (td, J=8.6,6.9 Hz, 2H), 3.67 (dd, J=16.5, 8.5 Hz, 2H), 3.23 (dd, J=16.4, 8.5 Hz,2H), 3.14-3.02 (m, 21H), 2.88 (t, J=6.9 Hz, 4H), 1.45 (dt, J=14.2, 5.0Hz, 13H), 1.27 (s, 15H).

Example 65:3-[8-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea

Beginning with INT-C9 and INT-IBC, Step A provided 100.3 mg (14%) of thetitle compound as a white solid. MS (m/z): 1227.65 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.82 (d, J=8.8 Hz, 2H), 7.77 (s, 2H), 7.55 (s,2H), 7.49 (d, J=8.8 Hz, 2H), 7.09 (s, 2H), 6.48 (s, 2H), 4.50-4.40 (m,2H), 3.75-3.65 (m, 2H), 3.35-3.20 (m, 2H), 3.17-2.96 (m, 20H), 2.92-2.83(m, 4H), 2.33 (s, 6H), 1.53-1.40 (m, 12H), 1.28 (s, 18H).

General Scheme for Synthesis of Diverse Amine Dimer Products:

Step A: To a round-bottom flask was added epoxide INT-17C (1 equiv), thedesired amine R²R³NH (2 equiv), and CH₃CN (0.16M). The resultingsolution was heated to reflux for 16 h. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:3-1:2) providing theaminoindanol INT-A1.

Step B: To a round-bottom flask was added aminoindanol INT-A1 (1 equiv)and tetrahydrofuran (0.2M), followed by the addition of phenol linkerINT-LGA (1.1 equiv) and heating to 40° C. To this slurry was added PPh3(2 equiv) and DIAD (1.5 equiv). The resulting solution was stirred for1.5 h at 40° C. The resulting mixture was concentrated under vacuum anddiluted with CH₂Cl₂. The residue was applied onto a silica gel columnwith ethyl acetate/petroleum ether (1:1) providing indane monomerINT-A2.

Step C: To a round-bottom flask was added indane monomer INT-A2 (1equiv), methanol (0.1M), and sodium hydroxide (3M_((aq)), 3 equiv). Theresulting solution was stirred for 1.5 h at 60° C. The resulting mixturewas concentrated under vacuum and diluted with CH₂Cl₂. The residue wasapplied onto a silica gel column with ethyl acetate (100%) providingindane amine monomer INT-A3.

Step D: To a round-bottom flask was added INT-A3 (1 equiv),N,N-dimethylformamide (DMF, 0.12M), and 1,4-di isocyanatobutane (0.40equiv). The resulting solution was stirred for 2 h at 60° C. Theresulting mixture was concentrated under vacuum and diluted with ofCH₂Cl₂. The residue was applied onto a silica gel column withchloroform/methanol (10:1) providing compounds of structure (I). Finalproducts were purified by preparative HPL with the following conditions:Column, XBridge C18 OBD Preparative Column, 19*250 mm, 5 um; mobilephase, water (0.05% TFA) and CH₃CN (10.0% CH₃CN up to 70.0% in 8 min);Detector, UV 254 nm. The final products were generally isolated as thefree base, TFA salts, or hydrochloride salts.

Example 66:3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Following the General Scheme with (2R)-2-methylpiperidine, Steps A-Dprovided 112.8 mg (15%) of the title compound as a white solid. MS(m/z): 1313.5 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz): δ 7.86 (d, J=8.8Hz, 4H), 7.39 (s, 2H), 7.35 (d, J=8.8 Hz, 4H), 7.13 (s, 2H), 6.12 (d,J=5.6 Hz, 2H), 4.16-4.04 (m, 2H), 3.60-3.46 (m, 16H), 3.40-3.20 (m, 8H),3.16-3.04 (m, 8H), 2.98-2.90 (m, 2H), 2.87-2.78 (m, 2H), 2.76-2.65 (m,2H), 2.32 (t, 8.8 Hz, 2H), 1.40-1.26 (m, 12H), 1.16 (d, J=6.0 Hz, 6H).

Example 67:3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(2S)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy])benzene)sulfonamido]ethoxy]ethoxyl)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2S)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Following the General Scheme with (2S)-2-methylpiperidine, Steps A-Dprovided 46.8 mg (26%) of the title compound as a white solid. MS (m/z):1313.5 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ 7.73 (d, J=6.8 Hz, 4H),7.34 (q, J=4.8 Hz, 6H), 7.16 (d, J=1.2 Hz, 2H), 5.80 (d, J=4.0 Hz, 2H),3.95 (q, J=4.8 Hz, 2H), 3.50-3.36 (m, 16H), 3.20-3.15 (m, 4H), 3.05-2.95(m, 10H), 2.90-2.80 (m, 2H), 2.52 (d, J=7.4 Hz, 4H), 2.10 (t, J=3.8 Hz,2H), 1.62 (d, J=9.6 Hz, 4H), 1.54-1.43 (m, 4H), 1.39-1.32 (m, 4H),1.31-1.20 (m, 4H), 1.18 (s, 2H), 1.00 (q, J=6.4 Hz, 6H).

Example 68:3-[2-(2-[2-[(4-[[(1S,2S)-2-[2-Azabicyclo[[2.2.1]heptan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.1]heptan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Following the General Scheme with 2-azabicyclo[2.2.1]heptane, Steps A-Dprovided 76.6 mg (14%) of the title compound as a white solid. MS (m/z):1309.5 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ 7.90 (d, J=8.0 Hz, 2H),7.42 (s, 2H), 7.35-7.26 (m, 4H), 7.09 (s, 2H), 6.00 (s, 2H), 3.93-3.20(m, 28H), 3.18-3.04 (m, 8H), 3.00-2.83 (m, 3H), 2.70-2.60 (m, 1H), 2.47(s, 3H), 2.13-1.80 (m, 2H), 1.80-1.35 (m, 15H).

Example 69:1-[2-(2-[2-[(4-[[(1S,2S)-2-[2-Azabicyclo[2.2.2]octan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy])benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.2]octan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy])benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Following the General Scheme with 2-azabicyclo[2.2.2]octane, Steps A-Dprovided 46.7 mg (18%) of the title compound as a white solid. MS (m/z):1337.5 [M+H]⁺. ¹H NMR (Methanol-d₄, 400 MHz): δ 7.86 (d, J=9.2 Hz, 4H),7.38 (s, 2H), 7.27 (d, J=8.8 Hz, 4H), 7.04 (s, 2H), 5.91 (d, J=6.8 Hz,2H), 3.76 (q, J=7.7 Hz, 2H), 3.57-3.46 (m, 18H), 3.30-3.27 (m, 4H),3.13-3.06 (m, 8H), 3.01 (d, J=9.6 Hz, 2E1), 2.86-2.72 (m, 6H), 2.05-1.93(m, 4H), 1.65-1.46 (m, 18H).

Example 70:3-[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.2.1]octan-8-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.2.1]octan-8-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Following the General Scheme with 8-azabicyclo[3.2.1]octane, Steps A-Dprovided 59.1 mg (30%) of the title compound as a white solid. MS (m/z):1337.0 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz): δ 7.78 (d, J=8.8 Hz, 4H),7.29 (s, 2H), 7.17 (d, J=9.2 Hz, 4H), 6.93 (s, 2H), 5.85 (d, J=6.4 Hz,2H), 3.75 (q, J=7.2 Hz, 2H), 3.50-3.47 (m, 3H), 3.47-3.35 (m, 11H),3.29-3.22 (m, 6H), 3.21-3.18 (m, 3H), 2.98 (t, J=5.6 Hz, 7H), 2.69 (q,J=8.2 Hz, 2H), 2.00-1.83 (m, 8H), 1.72 (d, J=2.8 Hz, 2H), 1.65-1.55 (m,6H), 1.43-1.31 (m, 6H), 1.29-1.15 (m, 611).

Example 71:1-[2-(2-[2-[(4-[[(1S,2S)-2-[9-Azabicyclo[3.3.1]nonan-9-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[9-azabicyclo[3.3.1]nonan-9-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Following the General Scheme with 9-azabicyclo[3.3.1]nonanehydrochloride (and added sodium hydroxide), Steps A-D provided 59.8 mg(16%) of the title compound as a white solid. MS (m/z): 1365.5 [M+H]⁺.¹H NMR (Methanol-d4, 400 MHz) δ 7.77 (d, J=8.8 Hz, 4H), 7.29 (s, 2H),7.16 (d, J=8.8 Hz, 4H), 6.93 (s, 2H), 5.81 (d, J=6.8 Hz, 2H), 4.34 (q,J=8.0 Hz, 2H), 3.48-3.37 (m, 16H), 3.27-3.17 (m, 6H), 3.03-2.96 (m, 8H),2.86 (s, 4H), 2.62 (q, J=8.2 Hz, 2H), 2.13-1.96 (m, 12H), 1.65-1.52 (m,4H), 1.45-1.37 (m, 12H).

Example 72:3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]ureaa; bis(trifluoroacetic acid)

Following the General Scheme with 1-methylpiperazine, Steps A-D provided72.8 mg (56%) of the title compound as a light yellow solid. MS (m/z):1315 [M+H]⁺. ¹H NMR (Methanol-d4, 300 MHz) δ 7.94-7.82 (m, 4H), 7.43 (d,J=1.8 Hz, 2H), 7.37-7.25 (m, 4H), 7.18-7.10 (m, 2H), 6.06 (d, J=5.9 Hz,2H), 3.70 (td, J=7.8, 5.9 Hz, 2H), 3.64-3.46 (m, 17H), 3.37 (s, 4H),3.32-3.20 (m, 6H), 3.16-2.83 (m, 20H), 2.80 (s, 6H), 1.53-1.42 (m, 4H).

Example 73:3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Following the General Scheme with 1-methylpiperazine and INT-L6C, StepsA-D provided 50.4 mg (39%) of the title compound as a light yellowsolid. MS (m/z): 672.5[M/2+H]⁺. ¹H NMR (Methanol-d4, 300 MHz) δ7.82-7.67 (m, 4H), 7.43 (dd, J=5.4, 3.5 Hz, 4H), 7.12 (s, 2H), 6.07 (d,J=6.0 Hz, 2H), 3.72 (q, J=7.3 Hz, 3H), 3.53 (dt, J=15.9, 4.7 Hz, 17H),3.38 (s, 3H), 3.33-2.79 (m, 27H), 2.70 (s, 4H), 2.27 (s, 6H), 1.46 (d,J=5.5 Hz, 4H).

Example 74:3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-Acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]1-[4-([[2-(2-[2-[(4-[[1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

To a 50-mL round-bottom flask was added the compound from Example 31(300 mg, 0.23 mmol, 1 equiv), CH₂Cl₂ (12 mL), triethylamine (0.163 mL),and acetyl chloride (0.050 mL). The resulting solution was stirred for0.5 h at 0-5° C. in a watertice bath. The resulting slurry wasconcentrated under vacuum. The crude product was purified by preparativeHPLC with the following conditions: Column, XBridge C18 OBD PreparativeColumn, 19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH₃CN(30.0% CH₃CN up to 52.0% in 8 min); Detector, UV 254 nm. This resultedin 200.5 mg (63%) of the title compound as a white solid. MS (m/z): 1371[M+H]⁺. ¹H NMR (Methanol-d4, 300 MHz) δ 7.99-7.89 (m, 4H), 7.54 (d,J=1.7 Hz, 2H), 7.44-7.34 (m, 4H), 7.15 (d, J=1.0 Hz, 2H), 6.48 (d, J=6.5Hz, 2H), 4.32 (q, J=7.9 Hz, 2H), 3.84 (s, 8H), 3.72-3.47 (m, 19H), 3.40(s, 5H), 3.34-3.18 (m, 8H), 3.11 (t, J=5.4 Hz, 8H), 2.16 (s, 6H), 1.48(d, J=6.2 Hz, 4H).

Example 75:3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-Acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Beginning with the compound in Example 32, the procedure for thesynthesis of Example 74 was employed to provide 150.9 mg (41%) of thetitle compound as a white solid. MS (m/z): 1399 [M+H]⁺. ¹H NMR(Methanol-d4, 300 MHz) δ 7.82-7.67 (m, 4H), 7.51-7.40 (m, 4H), 7.09-7.01(m, 2H), 6.43 (d, J=6.4 Hz, 2H), 4.26 (q, J=8.0 Hz, 2H), 3.77 (s, 9H),3.66-3.42 (m, 18H), 3.28-3.12 (m, 6H), 3.05 (q, J=5.8 Hz, 8H), 2.26 (s,6H), 2.10 (s, 6H), 1.49-1.38 (m, 4H).

Example 76:4-[(1S,2S)-4,6-dichloro-1-[4-[(2-[2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[4-(dimethylcarbamoyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)ethoxy]ethoxy]ethyl)sulfamoyl]phenoxy]-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperazine-1-carboxamide

To a 50-mL round-bottom flask was added the compound from Example 31(300 mg, 0.23 mmol, 1 equiv), CH₂Cl₂ (8 mL), N,N-dimethylcarbamoylchloride (75.2 mg, 0.70 mmol, 3 equiv), and triethylamine (0.162 mL).The resulting solution was stirred for 1 h at room temperature. Theresulting mixture was concentrated under vacuum. The crude product waspurified by preparative HPLC with the following conditions: Column,XBridge C18 OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water(0.05% TFA) and CH₃CN (30% CH₃CN up to 52% in 8 min); Detector, UV 254nm. This resulted in 236.9 mg (71%) of the title compound as a whitesolid. MS (m/z): 1429 [M+H]⁺. ¹H NMR (Methanol-d4, 300 MHz) δ 8.01-7.89(m, 4H), 7.56 (d, J=1.7 Hz, 2H), 7.45-7.34 (m, 4H), 7.17-7.10 (m, 2H),6.58 (d, J=6.9 Hz, 2H), 4.48 (q, J=8.2 Hz, 2H), 3.80-3.23 (m, 39H), 3.12(t, J=5.5 Hz, 9H), 2.91 (s, 12H), 1.54-1.43 (m, 4H).

Example 77:4-[(1S,2S)-4,6-dichloro-1-[4-[(2-[2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[4-(dimethylcarbamoyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)ethoxy]ethoxy]ethyl)sulfamoyl]-2-methylphenoxy]-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperazine-1-carboxamide;bis(trifluoreacetic acid)

Beginning with the compound in Example 32, the procedure for thesynthesis of Example 76 was employed to provide 198 mg (52%) of thetitle compound as a white solid. MS (m/z): 1455 [M+H]⁺. ¹H NMR(Methanol-d4, 300 MHz) δ 7.83-7.68 (m, 4H), 7.53-7.40 (m, 4H), 7.03 (d,J=1.7 Hz, 2H), 6.54 (d, J=6.6 Hz, 2H), 4.45 (q, J=8.1 Hz, 2H), 3.68 (dd,J=16.4, 8.6 Hz, 3H), 3.60-3.42 (m, 28H), 3.36 (d, J=9.1 Hz, 5H), 3.24(d, J=5.4 Hz, 4H), 3.05 (q, J=5.6 Hz, 8H), 2.86 (s, 12H), 2.27 (s, 6H),1.48-1.38 (m, 4H).

Scheme for the Synthesis of Example 78: Example 78:3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Step A: To a 50-mL sealed tube was added tert-butyl(3S)-3-(methanesulfonyloxy)piperidine-1-carboxylate (5 g, 17.9 mmol, 1equiv), methanol (15 mL), and methyl(propan-2-yl)amine (3.9 g, 53.3mmol, 3 equiv). The resulting solution was stirred for 72 hrs at 90° C.The resulting mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column with CH₂Cl₂/methanol (0-5%) providing 2g (44%) of tart-butyl(3R)-3-[methyl(propan-2-yl)amino]piperidine-1-carboxylate as a yellowoil.

Step B: To a 100-mL round-bottom flask was added tert-butyl(3R)-3-[methyl(propan-2-yl)amino]piperidine-1-carboxylate (1.7 g, 6.63mmol, 1 equiv) and hydrogen chloride in methanol (40 mL). The finalreaction mixture was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum to provide 1.52 g (100%)of (3R)—N-isopropyl-N-methylpiperidin-3-amine dihydrochloride as a whitesolid.

Step C: To a 50-mL round-bottom flask was added epoxide INT-17C (300 mg,1.49 mmol, 1 equiv), (3R)—N-isopropyl-N-methylpiperidin-3-aminedihydrochloride (684 mg, 2.98 mmol, 2 equiv), MeCN (10 mL), and sodiumhydroxide(3M_((aq)), 3 mL). The resulting solution was stirred for 1 hat 70° C. in an oil bath. The resulting solution was extracted with 3×50mL of ethyl acetate and the organic layers combined and concentratedunder vacuum. The residue was applied onto a silica gel column withCH₂Cl₂/methanol (8:1) providing 530 mg (99%) of(1R,2R)-4,6-dichloro-1-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-2-ol(INT-A4) as a red oil.

Step D: To a 50-mL round-bottom flask was added aminoindanol INT-A4 (570mg, 1.60 mmol, 1 equiv), phenol INT-L6A (716 mg, 1.77 mmol, 1.1 equiv),THF (3.7 mL), and PPh3 (627 mg, 2.39 mmol, 1.5 equiv). Heating at 40° C.in an oil bath DIAD (0.47 mL, 1.5 equiv) was added dropwise withstirring over 30 min. The resulting solution was stirred for 1 h at 40°C. in an oil bath. The residue was applied onto a silica gel column withCH₂Cl₂/methanol (10:1) providing 600 mg (51%) of tert-butylN-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamate(INT-A5) as a yellow oil.

Step E: To a 100-mL round-bottom flask was added INT-A5 (600 mg, 0.81mmol, 1 equiv), CH₂Cl₂ (10 mL), and TFA (2 mL). The resulting solutionwas stirred for 1 h at room temperature. The pH value of the solutionwas adjusted to 8 with saturated aqueous sodium bicarbonate andextracted with 3×50 mL of CH₂Cl₂. The organic layers were combined andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with CH₂Cl₂/methanol (8:1) providing 420 mg (81%) ofN-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene-1-sulfonamide(INT-A6) as a yellow oil.

Step F: To a 50-mL round-bottom flask was added amine INT-A6 (400 mg,0.62 mmol, 1 equiv), DMF (5 mL), and 1,4-diisocyanatobutane (68 mg, 0.25mmol, 0.40 equiv). The resulting solution was stirred for 1 h at 60° C.in an oil bath. The resulting mixture was concentrated under vacuum. Thecrude product was purified by preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm, 5 um;mobile phase, water (0.05% TFA) and CH₃CN (25.0% CH₃CN up to 45.0% in 8min); Detector, UV 254 nm.

Example 78:3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; bis(trifluoroacetic acid)

Steps A-F provided 203.1 mg (20%) of the title compound as a whitesolid. MS (m/z): 714.5 [M/2+H]⁺. ¹H NMR (Methanol-d4, 300 MHz) δ7.91-7.81 (m, 4H), 7.42 (d, J=1.7 Hz, 2H), 7.30 (d, J=8.5 Hz, 4H), 7.11(d, J=2.4 Hz, 2H), 6.18 (m, 2H), 3.98-3.66 (m, 4H), 3.54 (dq, J=5.6, 2.0Hz, 8H), 3.47 (t, J=5.5 Hz, 10H), 3.29 (m, 3H), 3.27-3.23 (m, 4H),3.12-2.99 (m, 10H), 2.94 (m, 4H), 2.77-2.62 (m, 6H), 2.58 (m, 3H), 2.08(m, 2H), 1.89 (m, 2H), 1.70 (m, 4H), 1.49-1.38 (m, 4H), 1.31 (m, 10H),1.20 (d, J=6.5 Hz, 2H).

General Scheme for Synthesis of Disubstituted Sulfonamide DimerProducts:

Step A: To a round-bottom flask was added aminoindanol INT-18 (1 equiv)and tetrahydrofuran (0.2M), followed by the addition of phenol linkerTNT-L6 (0.1 equiv) and heating to 40° C. To this slurry was added PPh3(2 equiv) and DIAD (1.5 equiv). The resulting solution was stirred for1-3 h at 40° C. The resulting mixture was concentrated under vacuum anddiluted with CH₂Cl₂. The residue was applied onto a silica gel columnwith petroleum ether/ethyl acetate (1:1) providing indane monomerINT-D1.

Step B: To a round-bottom flask was added indane monomer INT-D1 (1equiv), methanol (0.1M), and sodium hydroxide (3M_((aq)), 3-5 equiv).The resulting solution was stirred for 1-2 h at 60° C. The resultingmixture was concentrated under vacuum and diluted with CH₂Cl₂. Theresidue was applied onto a silica gel column with CH₂Cl₂/methanol (10:1)providing indane amine monomer INT-D2.

Step C: To a round-bottom flask was added INT-D2 (1 equiv),dimethylformamide (DMF, 0.1M), and 1,4-diisocyanatobutane (0.4-0.5equiv). The resulting solution was stirred for 2 h at 60° C. Theresulting mixture was concentrated under vacuum and diluted with ofCH₂Cl₂. The residue was applied onto a silica gel column withchloroform/methanol (10:1) providing the desired dimer of structure (I).Final products were purified by preparative HPLC. The final productswere generally isolated as the free based amines, TFA salts, orhydrochloride salts.

Step D (for Boc-protected intermediates): To a round-bottom flask wasadded Boc-protected dimer (I) (1 equiv) and 5:1 CH₂Cl₂:TFA (˜0.05M). Theresulting solution was stirred for 2 h at room temperature. Theresulting mixture was concentrated under vacuum. The crude product waspurified by preparative HPLC. The final products were generally isolatedas the free based amines, TFA salts, or hydrochloride salts.

Example 79:3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;hydrochloride

Beginning with INT-LCD and INT-I8F, Steps A-D provided Example 79 whichwas purified by preparative HPLC with the following conditions: Column,XBridge Preparative OBD C18 Column, 19*250 mm, 5 um; mobile phase, water(0.05% HCl) and CH₃CN (40.0% CH₃CN up to 70.0% in 8 min); Detector, UV254 nm. This resulted in 129.2 mg (48%) of the title compound as ayellow solid. MS (m/z): 1370.85 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ7.60 (d, J=15.2 Hz, 6H), 6.45 (s, 2H), 6.30 (s, 2H), 4.70 (d, J=3.2 Hz,2H), 3.95-3.80 (m, 6H), 3.70-3.50 (m, 20H), 3.40-3.35 (m, 8H), 3.17 (s,4H), 3.05 (t, J=5.4 Hz, 4H), 2.30-2.10 (m, 18H), 1.88 (5, 2H), 1.54 (s,4H).

Example 80:1-[2-(2-[2-[(3-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,4-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Beginning with INT-L6D and INT-I8C, Steps A-C provided Example 80 whichwas purified by preparative HPLC with the following conditions: Column,XBridge BEH130 Preparative C18 OBD Column, 19*150 mm, 5 um; mobilephase, water (0.05% NH₄OH) and CH₃CN (75.0% CH₃CN up to 84.0% in 9 min);Detector, UV 254 nm. This resulted in 91.5 mg (28%) of the titlecompound as a white solid. MS (m/z): 1261.20 [M+]⁺. ¹H NMR (Methanol-d4,400 MHz) δ 7.56 (s, 4H), 7.43 (d, J=1.6 Hz, 2H), 6.50 (d, J=1.2 Hz, 2H),5.68 (d J=2.4 Hz, 2H), 4.82-4.78 (m, 2H), 3.58 (q, J=5.0 Hz, 8H),3.55-3.50 (m, 8H), 3.42-3.37 (m, 2H), 3.35-3.30 (m, 4H), 3.13 (s, 4H),3.08-2.96 (m, 6H), 2.30 (s, 12H), 2.15 (d, J=9.6 Hz, 12H), 1.50 (s, 4H).

Example 81:3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Beginning with INT-L6E and INT-I8F, Steps A-D provided Example 81 whichwas purified by preparative HPLC with the following conditions: Column,XBridge Preparative OBD C₁₈ Column, 19*250 mm, 5 um; mobile phase, water(10 mmol/L NH₄HCO₃+0.1% NH₄OH) and CH₃CN (50.0% CH₃CN up to 60.0% in 13min); Detector, UV 254 nm. This resulted in 113.6 mg (30%) of the titlecompound as a light yellow solid. MS (m/z): 1371.75 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.83 (s, 2H), 7.54 (s, 2H), 7.48 (s, 2H), 7.01(d, J=1.8 Hz, 2H), 6.88 (d, J=6.0 Hz, 2H), 4.61 (d, J=8.0 Hz, 2H),3.87-3.71 (m, 8H), 3.70-3.51 (m, 20H), 3.50-3.33 (m, 8H), 3.21 (d, J=6.0Hz, 4H), 3.11 (t, J=5.6 Hz, 4H), 2.71 (s, 6H), 2.30-2.11 (m, 10H), 1.83(s, 2H), 1.56 (s, 5H).

Example 82:3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Beginning with INT-L6E and INT-I8C, Steps A-C provided Example 82 whichwas purified by preparative HPLC with the following conditions(2π-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge C18 OBD PreparativeColumn, 19*250 mm, 5 um; mobile phase, water (0.05% NH₄OH) and CH₃CN(85.0% CH₃CN up to 89.0% in 11 min); Detector, UV 254 nm. This resultedin 74.8 mg (14%) of the title compound as a white solid. MS (m/z):1261.55 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ 7.77 (s, 2H), 7.42 (s,2H) 7.30 (s, 2H), 7.09 (s, 2H), 5.99 (d, J=6.2 Hz, 2H), 3.63-3.42 (m,18H), 3.30 (q, J=5.6 Hz, 6H), 3.20-3.04 (m, 8H), 2.91 (dd, J=16.4, 8.0Hz, 2H), 2.66 (s, 6H), 2.37 (s, 12H), 2.22 (s, 6H), 1.53 (s, 4H).

Example 83:1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amido)butyl]urea;hydrochloride

Beginning with INT-L6F and INT-18F, Steps A-D provided Example 83 whichwas purified by preparative HPLC with the following conditions: Column,XBridge Preparative OBD C18 Column, 19*250 mm, 5 um; mobile phase, water(0.05% HCl) and CH₃CN (20.0% CH₃CN up to 70.0% in 8 min); Detector, UV254 nm. This resulted in 317.6 mg (64%) of the title compound as a lightyellow solid. MS (m/z): 1380.80 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ7.66 (d, J=11.2 Hz, 2H), 7.65 (s, 2H), 7.62 (s, 2H), 6.70 (s, 4H), 4.67(s, 2H), 3.99-3.80 (m, 8H), 3.68-3.48 (m, 19H), 3.46-3.28 (m, 7H), 3.21(s, 4H), 3.11 (t, J=5.2 Hz, 4H), 2.14 (s, 6H), 2.30-2.10 (m, 6H),1.93-1.78 (m, 2H), 1.57 (s, 4H).

Example 84:1-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Beginning with INT-L6F and INT-18C, Steps A-C provided Example 84 whichwas purified by preparative HPLC with the following conditions: Column,XBridge C18 OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water(0.05% TFA) and CH₃CN (45.0% CH₃CN up to 65.0% in 8 min); Detector, UV254 nm. This resulted in 109.6 mg (30%) of the title compound as a whitesolid. MS (m/z): 1269.45 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ 7.59(t, J=13.4 Hz, 4H), 7.44 (s, 2H), 6.93 (s, 2H), 5.92 (d, J=4.0 Hz, 2H),3.72-3.65 (m, 3H), 3.60-3.50 (m, 16H), 3.38-3.29 (m, 5H), 3.13-3.08 (m,8H), 2.93 (dd, J=16.8, 5.6 Hz, 2H), 2.32 (s, 12H), 2.15 (s, 6H), 1.49(s, 4H).

Example 85:3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-difluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-difluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; bis(trifluoroacetic acid)

Beginning with INT-L6H and INT-18F, Steps A-D provided Example 85 whichwas purified by preparative HPLC with the following conditions: Column,XBridge C18 OBD Preparative Column, 19 mm*250 mm, 5 um; mobile phase,water (0.05% TFA) and CH₃CN (25% CH₃CN up to 65% in 8 min); Detector, UV254 nm. This resulted in 192.3 mg (57%) of the title compound as a whitesolid. MS (m/z): 1387 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ 7.59 (d,J=7.2 Hz, 4H), 7.46 (d, J=1.8 Hz, 2H), 7.22-7.16 (m, 2H), 5.89 (d, J=4.9Hz, 2H), 3.89 (q, J=6.4 Hz, 2H), 3.62-3.47 (m, 17H), 3.31-3.22 (m, 5H),3.20-3.06 (m, 10H), 3.04-2.93 (m, 4H), 2.69 (s, 2H), 2.56-2.40 (m, 4H),1.97-1.88 (m, 2H), 1.78 (d, J=12.4 Hz, 2H), 1.54-1.36 (m, 8H).

Example 86:4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3,5-difluorophenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]-3,5-difluorobenzenesulfonamide;bis(trifluoroacetic acid)

Beginning with INT-L6H and INT-I8C, Steps A-C provided Example 86 whichwas purified by preparative HPLC with the following conditions: Column,XBridge C18 OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water(0.05% TFA) and CH₃CN (25.0% CH₃CN up to 38.0% in 9 min); Detector, UV254 nm. This resulted in 225.1 mg (52%) of the title compound as a whitesolid. MS (m/z): 1277 [H+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ 7.70-7.59(m, 4H), 7.57 (d, J=1.8 Hz, 2H), 7.07-7.01 (m, 2H), 6.31 (d, J=4.1 Hz,2H), 4.54 (ddd, J=8.4, 5.7, 4.1 Hz, 2H), 3.72 (dd, J=17.5, 8.5 Hz, 2H),3.61-3.46 (m, 17H), 3.27 (t, J=5.4 Hz, 5H), 3.16-3.05 (m, 8H), 3.02 (s,12H), 1.47 (p, J=3.3 Hz, 4H).

Example 87:3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Beginning with INT-L6G and INT-18F, Steps A-D provided Example 87 whichwas purified by preparative HPLC with the following conditions: Column,XBridge C18 OBD Preparative Column, 19 mm*250 mm, 5 um; mobile phase,water (0.05% TFA) and CH₃CN (15.0% CH₃CN up to 65.0% in 8 min);Detector, UV 254 nm. This resulted in 254 mg (50%) of the title compoundas a white solid. MS (m/z): 1379 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ7.74 (d, J=11.1 Hz, 2H), 7.49-7.42 (m, 4H), 7.17-7.12 (m, 2H), 6.17 (d,J=5.8 Hz, 2H), 3.86 (q, J=7.4 Hz, 2H), 3.62-3.42 (m, 16H), 3.41-3.24 (m,8H), 3.15-2.98 (m, 13H), 2.88 (s, 2H), 2.64 (s, 8H), 1.97 (s, 3H), 1.88(s, 1H), 1.58 (dd, 12.8, 8.9 Hz, 2H), 1.51-1.42 (m, 4H).

Example 88:3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Beginning with INT-L6G and INT-I8C, Steps A-C provided Example 88 whichwas purified by preparative HPLC with the following conditions: Column,XBridge Preparative C18 OBD Column, 19*150 mm, 5 um; mobile phase, water(0.05% NH₄OH) and CH₃CN (5.0% CH₃CN up to 75.0% in 1 min, up to 86.0% in6 min); Detector, UV 254/220 nm. This resulted in 80.2 mg (18%) of thetitle compound as a white solid. MS (m/z): 1269 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.72 (d J=11.2 Hz, 2H), 7.50-7.39 (m, 4H),7.16-7.10 (m, 2H), 5.97 (d, J=5.8 Hz, 2H), 3.61-3.41 (m, 19H), 3.37-3.20(m, 6H), 3.10 (t, J=5.4 Hz, 9H), 2.90 (dd, J=16.6, 7.4 Hz, 2H), 2.63 (s,6H), 2.34 (s, 12H), 1.51-1.43 (m, 4H).

Example 89:3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Beginning with INT-L6I and INT-18F, Steps A-D provided Example 89 whichwas purified by preparative HPLC with the following conditions: Column,XBridge Preparative OBD C18 Column, 19*250 mm, 5 um; mobile phase, water(0.05% TFA) and CH₃CN (55.0% CH₃CN up to 80.0% in 8 min); Detector, UV254 nm. This resulted in 234.1 mg (74%) of the title compound as a whitesolid. MS (m/z): 690.5 [M/2+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ 7.66(d, J=8.1 Hz, 2H), 7.45 (d, J=1.7 Hz, 2H), 7.38 (d, J=12.2 Hz, 2H),7.19-7.14 (m, 2H), 6.04 (d, J=5.5 Hz, 2H), 3.74 (s, 2H), 3.63-3.46 (m,15H), 3.31-3.22 (m, 4H), 3.19-2.92 (m, 13H), 2.75 (s, 2H), 2.63 (d,J=9.6 Hz, 2H), 2.54 (s, 3H), 2.19 (s, 5H), 1.95 (s, 3H), 1.85 (s, 2H),1.68 (s, 2H), 1.55 (d, J=10.6 Hz, 2H), 1.47 (d, J=3.7 Hz, 3H).

Example 90:3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;bis(trifluoroacetic acid)

Beginning with INT-L6I and INT-18C, Steps A-C provided Example 90 whichwas purified by preparative HPLC with the following conditions: Column,XSelect CSH Preparative C18 OBD Column, 19*250 mm, 5 um; mobile phase,water (0.05% TFA) and CH₃CN (25.0% CH₃CN up to 40.0% in 10 min);Detector, UV 254 nm. This resulted in 216.8 mg (58%) of the titlecompound as a white solid. MS (m/z): 1291 [M+Na]⁺ ¹H NMR (Methanol-d4,400 MHz) δ 7.75-7.67 (m, 2H), 7.55 (d, J=1.7 Hz, 2H), 7.41 (d, J=11.6Hz, 2H), 7.17-7.07 (m, 2H), 6.46 (d, J=6.7 Hz, 2H), 4.50 (td, J=8.5, 6.6Hz, 2H), 3.74-3.63 (m, 3H), 3.61-3.46 (m, 18H), 3.31-3.20 (m, 6H),3.20-3.01 (m, 25H), 2.26 (d, J=7.6 Hz, 7H), 1.46 (td, J=6.4, 3.2 Hz,4H).

Scheme for the Synthesis of Pyrrolidinone Linkers:

Step A: To a 500-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added 2-(2-aminoethoxy)ethan-1-ol (16.1g, 153 mmol, 1 equiv), CH₂Cl₂ (160 mL), and triethylamine (22.4 mL, 1.05equiv). This was followed by the addition of CbzCl (28.7 g, 168.24 mmol,1.1 equiv) dropwise with stirring at 5-10° C. The resulting solution wasstirred overnight at room temperature. The reaction was then quenched bythe addition of 100 mL of water and extracted with 3×100 mL of CH₂Cl₂.The organic layers were combined and washed with 1×100 mL of brine,dried over anhydrous sodium sulfate, filtered, and concentrated undervacuum. The solid was dried in an oven under reduced pressure. Theresidue was applied onto a silica gel column with petroleum ether/ethylacetate (1:1) providing 32 g (87%) of benzylN-[2-(2-hydroxyethoxy)ethyl]carbamate (INT-P1) as a yellow oil.

Step B: To a 250-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added alcohol INT-P1 (5 g, 20.90 mmol,1 equiv), phthalimide (3.07 g, 20.9 mmol, 1 equiv), and tetrahydrofuran(49 mL). This was followed by the addition of PPh₃ (8.22 g, 31.34 mmol,1.5 equiv) in several portions at 40° C. To this was added DIAD (6.17mL, 1.5 equiv) dropwise with stirring at 40° C. over 30 min. Theresulting solution was stirred for 1 h at 40° C. in an oil bath. Theresulting slurry was diluted with water and extracted with 3×100 mL ofethyl acetate. The organic layers combined and concentrated undervacuum. The residue was applied onto a silica gel column with petroleumether/ethyl acetate (1:1) providing 6.5 g (84%) of benzylN-[2-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)ethoxy]ethyl] carbamate(INT-P2) as a yellow oil.

Step C: To a 1-L round-bottom flask purged and maintained with an inertatmosphere of nitrogen was added phthalimide INT-P2 (6.5 g, 17.6 mmol, 1equiv), ethanol (500 mL), and NH₂NH₂.H₂O (8.8 g, 10 equiv). Theresulting solution was stirred for 3 h at 85° C. in an oil bath. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with CH₂Cl₂/methanol (5:1) providing 4 g (95%)of benzyl N-[2-(2-aminoethoxy)ethyl]carbamate (INT-P3) as a yellow oil.

Step D: To a 250-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added Boc-Met-OH (3.77 g, 15.1 mmol, 1equiv), amine INT-P3 (3.6 g, 15.1 mmol, 1 equiv), THF (54 mL), HOBT(2.04 g, 15.1 mmol, 1 equiv), and diisopropylethylamine (5 mL, 2 equiv).This was followed by the addition of DIC (2.5 mL, 1.05 equiv) dropwisewith stirring at 0° C. The resulting solution was stirred for 1 h atroom temperature. The resulting mixture was concentrated under vacuum.The residue was applied onto a silica gel column with H₂O/CH₃CN (3:2)providing 5.2 g (73%) of tert-butylN-[(1S)-1-[[2-(2-[[(benzyloxy)carbonyl]amino]ethoxy)ethyl]carbamoyl]-3-(methylsulfonyl)propyl]carbamate(INT-P4) as a yellow oil.

Step E: To a 250-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added INT-P4 (5.2 g, 11.07 mmol, 1equiv) and iodomethane (50 mL). The resulting solution was stirred for 3days at room temperature. The resulting mixture was concentrated undervacuum. This resulted in 5.3 g (99%) of tert-butylN-[(1S)-1-[[2-(2-[[(benzyloxy)carbonyl]amino]ethoxy)ethyl]carbamoyl]-3-(dimethylsulfaniumyl)propyl]carbamate (INT-P5) as a lightyellow oil.

Step F: To a 250-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added INT-P5 (5.3 g, II 0.8 mmol, 1equiv), DMF (60 mL), CH₂Cl₂ (60 mL), and lastly sodium hydride (900 mg,37.5 mmol, 3.2 equiv) in portions. The resulting slurry was stirred for2.5 h at 0° C. in an ice/salt bath. The resulting mixture wasconcentrated under vacuum. The residue was diluted with CH₂Cl₂ andwashed with 3×100 mL of brine. The organic layer was dried overanhydrous sodium sulfate, filtered, and concentrated under vacuumproviding 4.6 g (93%) of benzylN-(2-[2-[(3S)-3-[[(tert-butoxy)carbonyl]amino]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)carbamate(INT-P6) as a yellow oil.

Step G: To a 250-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added pyrrolidinone INT-P6 (4.5 g,10.68 mmol, 1 equiv), CH₂Cl₂ (50 mL), and trifluoroacetic acid (8 mL).The resulting solution was stirred for 3 h at room temperature. Theresulting mixture was concentrated under vacuum. The reaction wasquenched by the addition of 100 mL of water. The pH of the solution wasadjusted to 8 with saturated aqueous sodium bicarbonate and extractedwith 5×100 mL of ethyl acetate. The organic layers were combined, driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.This resulted in 3.4 g (100%) of benzylN-(2-[2-[(3S)-3-amino-2-oxopyrrolidin-1-yl]ethoxy]ethyl) carbamate(INT-P7) as a yellow oil.

Step H: To a 250-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added CH₂Cl₂ (20 mL), triethylamine(4.6 mL, 2.9 equiv), and amine INT-P7 (3.3 g, 10.3 mmol, 0.9 equiv). Tothis mixture was added a solution of4-(benzyloxy)-3-methylbenzene-1-sulfonyl chloride (INT-L3 with R¹=m-Me,3.4 g, 11.5 mmol, 1 equiv) in CH₂Cl₂ (30 mL) dropwise with stirring over20 min. The resulting solution was stirred for 2 h at room temperature.The reaction was quenched by the addition of 100 mL of water andextracted with 3×200 mL of ethyl acetate. The organic layers werecombined and washed with 1×100 mL of brine. The organic layer was driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The residue was applied onto a silica gel column with petroleumether/ethyl acetate (3:7) providing 4.2 g (63%) of benzylN-(2-[2-[(3S)-3-[[4-(benzyloxy)-3-methylbenzene]sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)carbamate(INT-P8) as a yellow oil.

Step I: To a 500-mL round-bottom flask purged and maintained with aninert atmosphere of hydrogen was added benzyl ether INT-P8 (4.2 g, 7.22mmol, 1 equiv) and methanol (50 mL). This was followed by the additionof palladium on carbon (2.1 g, 60% of water). The resulting slurry wasstirred for 2 days at room temperature. The solids were filtered out.The mixture was dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. This resulted in 2.3 g (88%) ofN-[(3S)-1-[2-(2-aminoethoxy)ethyl]-2-oxopyrrolidin-3-yl]-4-hydroxy-3-methylbenzene-1-sulfonamide(INT-P9) as a white solid.

Step J: To a 500-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added amine INT-P9 (2.3 g, 6.43 mmol, 1equiv), methanol (30 mL), triethylamine (0.2 mL, 0.20 equiv), and ethyl2,2,2-trifluoroacetate (2.35 mL, 3 equiv). The resulting solution wasstirred for 3 h at room temperature. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with hexane/ethyl acetate (3:7) providing 2 g (69%) of2,2,2-trifluoro-N-(2-[2-[(3S)-3-[(4-hydroxy-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)acetamide(INT-P10) as a white solid.

Scheme for the Synthesis of Pyrrolidinone Dimer Products: Example 91:1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl]carbamoyl]amino]butylurea

Step A: To a 50-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added phenol INT-P10 (300 mg, 0.66mmol, 1 equiv), aminoindanol INT-18C (163 mg, 0.66 mmol, 1 equiv), andTHF (1.5 mL). This was followed by the addition of PPh₃ (260 mg, 0.99mmol, 1.5 equiv) at 40° C. To this was added DIAD (0.2 mL, 1.5 equiv)dropwise with stirring at 40° C. over 30 min. The resulting solution wasstirred for 1 h at 40° C. in an oil bath. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with hexane/ethyl acetate (1:2) providing 400 mg (89%) ofN-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-2,2,2-trifluoroacetamide(INT-P11) as a yellow oil.

Step B: To a 250-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added monomer intermediate INT-P11 (400mg, 0.59 mmol, 1 equiv) and methanol (10 mL). This was followed by theaddition of sodium hydroxide (3M_((aq)), 1.5 mL). The resulting solutionwas stirred for 1 h at 60° C. in an oil bath. The resulting solution wasdiluted with water and extracted with 3×100 mL of ethyl acetate. Theorganic layers were combined and washed with 1×100 mL of brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with CH₂Cl₂/methanol (5:1) providing 320 mg (93%) ofN-[(3S)-1-[2-(2-aminoethoxy)ethyl]-2-oxopyrrolidin-3-yl]-4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene-1-sulfonamide(INT-P12) as a yellow oil.

Step C: To a 100-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added amine INT-P12 (320 mg, 0.55 mmol,1 equiv), DMF (3.6 mL), and 1,4-diisocyanatobutane (34.5 mg, 0.25 mmol,0.45 equiv). The resulting solution was stirred for 2 h at 60° C. in anoil bath. The resulting mixture was concentrated under vacuum andpurified by preparative HPLC as below.

Example 91:1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea

Crude compound of Steps A-C was purified by preparative HPLC with thefollowing conditions: Column, XBridge Preparative OBD C18 Column, 19*250mm, 5 um; mobile phase, water (0.05% NH₄OH) and CH₃CN (73.0% CH₃CN to86.0% in 8 min); Detector, UV 220 nm. This resulted in 139 mg (19%) ofthe title compound as a white solid. MS (m/z): 1311 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.85-7.74 (m, 4H), 7.46-7.37 (m, 4H), 7.11-7.06(m, 2H), 5.96 (d, J=6.1 Hz, 2H), 4.05 (dd, J=9.8, 8.5 Hz, 2H), 3.60-3.31(m, 18H), 3.31-3.20 (m, 6H), 3.12 (t, J=5.3 Hz, 4H), 2.89 (dd, J=16.5,7.8 Hz, 2H), 2.34 (s, 12H), 2.25 (s, 8H), 1.78 (dq, J=12.4, 9.3 Hz, 2H),1.49 (p, J=3.2 Hz, 4H).

Scheme for Synthesis of Cyano-Containing Pyrrolidinone Dimer Product:Example 92:1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-Choro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl]carbamoyl]amino]butyl)urea;bis(trifluoroacetic acid)

Step A: To a 50-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added phenol INT-P10 (500 mg, 1.1 mmol,1 equiv), aminoindanol INT-18B (320 mg, 1.1 mmol, 1 equiv), and THF (2.6mL). This was followed by the addition of PPh₃ (434 mg, 1.65 mmol, 1.5equiv) at 40° C. To this slurry was added DIAD (0.33 mL) dropwise withstirring at 40° C. over 30 min. The resulting solution was stirred for 1h at 40° C. in an oil bath. The resulting mixture was concentrated widervacuum. The residue was applied onto a silica gel column with petroleumether/ethyl acetate (2/1) providing 570 mg (71%) ofN-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4-bromo-6-chloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-2,2,2-trifluoroacetamide (INT-P13) as a yellow oil.)

Step B: To a 50-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added INT-P13 (570 mg, 0.79 mmol, 1.00equiv), NMP (6 mL), Zn(CN)₂ (55.4 mg, 0.6 equiv), and Pd(PPh₃)₄ (91 mg,0.08 mmol, 0.1 equiv). The resulting solution was stirred for overnightat 100° C. in an oil bath. The reaction was then quenched by theaddition of 10 ml, of water and extracted with 3×20 mL of ethyl acetate.The organic layers were combined and washed with 3×50 mL of brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1/1) providing 400 mg (76%)ofN-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-2,2,2-trifluoroacetamide(INT-P14) as a yellow oil.

Step C: To a 100-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added INT-P14 (400 mg, 0.60 mmol, 1equiv), methanol (7 mL), and sodium hydroxide (3M_((aq)), 1 mL). Theresulting solution was stirred for 2 h at room temperature. Theresulting solution was extracted with 3×50 mL of ethyl acetate and theorganic layers combined. The resulting mixture was washed with 1×50 mLof brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with CH₂Cl₂/methanol (5/1) providing 300 mg (87%) ofN-[(3S)-1-[2-(2-aminoethoxy)ethyl]-2-oxopyrrolidin-3-yl]-4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene-1-sulfonamide(INT-P15) as a yellow oil.

Step D: To a 50-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was added amine INT-P15 (144 mg, 0.25mmol, 1 equiv), DMF (2 mL), and 1,4-diisocyanatobutane (0.012 mL, 0.4equiv). The resulting solution was stirred for 2 h at 60° C. in an oilbath. The resulting mixture was concentrated under vacuum and purifiedby preparative HPLC as below.

Example 92:1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-3-(4-[[(2-[2-[(3S)-3-[4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl]carbamoyl]amino]butyl)urea;bis(trifluoroacetic acid)

Crude compound of Steps A-D was purified by preparative HPLC with thefollowing conditions: Column, XBridge Shield RP18 OBD Column, 19*150 mm,5 um; mobile phase, water (0.05% TFA) and CH₃CN (15.0% CH₃CN up to 40.0%in 10 min); Detector, UV 254 nm. This resulted in 51.5 mg (14%) of thetitle compound as a white solid. MS (m/z): 1293 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.91-7.79 (m, 6H), 7.49 (d, J=8.8 Hz, 2H),7.45-7.39 (m, 2H), 6.52 (d, J=6.7 Hz, 2H), 4.54 (td, J=8.5, 6.6 Hz, 2H),4.07 (dd, J=9.9, 8.5 Hz, 2H), 3.81 (dd, J=16.7, 8.5 Hz, 2H), 3.59-3.32(m, 19H), 3.22 (t, J=5.4 Hz, 4H), 3.07 (s, 17H), 2.31 (s, 8H), 1.80 (dq,J=12.6, 9.3 Hz, 2H), 1.52-1.44 (m, 4H).

Representative Scheme for Synthesis of Cyclic-Substituted SulfonamideLinkers:

Step A: To a 250-mL round-bottom flask was added2-(2-chloroethoxy)ethan-1-ol (7.8 g, 62.62 mmol, 1 equiv) and water (300mL). This was followed by the addition of a solution of sodium azide(7.7 g, 118.4 mmol, 2 equiv) in water (40 mL) dropwise with stirring.The resulting solution was stirred overnight at 80° C. The reactionmixture was cooled to 0° C. with a watertice bath and extracted with3×500 mL of CH₂Cl₂. The organic layers were combined, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuumproviding 10 g (crude) of 2-(2-azidoethoxy)ethan-1-ol (INT-Y1) as acolorless oil.

Step B: To a 500-mL round-bottom flask was added azidoalcohol INT-Y1 (10g crude from Step A, theoretical 62.6 mmol, 1 equiv), dichloromethane(300 mL), 4-methylbenzene-1-sulfonyl chloride (18 g, 94.42 mmol, 1.3equiv), and triethylamine (10 mL, 1.15 equiv). The resulting solutionwas stirred for 2 h at room temperature. The reaction was then quenchedby the addition of 50 mL of water and extracted with 3×300 mL ofdichloromethane. The organic layers were combined, dried over anhydroussodium sulfate, filtered, and concentrated under vacuum. The residue wasapplied onto a silica gel column with petroleum ether/ethyl acetate(1:3) providing 15 g (69%) of1-[[2-(2-azidoethoxy)ethoxy]sulfonyl]-4-methylbenzene (INT-Y2) as acolorless oil.

Step C: To a 100-mL round-bottom flask was added tert-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate (700 mg, 3.74 mmol, 1 equiv),DMF (30 mL), and tosylate INT-Y2 (900 mg, 3.15 mmol, 0.84 equiv). Thiswas followed by the addition of sodium hydride (300 mg, 12.50 mmol, 3.34equiv) in several portions at 0° C. The resulting slurry was stirredovernight at 40° C. The resulting mixture was diluted with 50 mL ofethyl acetate and quenched by the addition of 50 mL of water. Theresulting solution was extracted with 2×150 mL of ethyl acetate and theorganic layers combined. The resulting mixture was washed with 2×150 mLof brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. This resulted in 940 mg (84%) of tert-butyl(3R)-3-[2-(2-azidoethoxy)ethoxy]pyrrolidine-1-carboxylate (INT-Y3) as alight brown solid.

Step D: To a 100-mL round-bottom flask was added azide INT-Y3 (940 mg,3.13 mmol, 1 equiv), CH₂Cl₂ (50 mL), and trifluoroacetic acid (12 mL).The resulting solution was stirred for 30 min at room temperature. ThepH value of the solution was adjusted to 12 with saturated aqueouspotassium carbonate and extracted with 2×150 mL of CH₂Cl₂. The combinedorganic layers were washed with 2×150 mL of brine, dried over anhydroussodium sulfate, filtered, and concentrated under vacuum. This resultedin 630 mg (crude) of (3R)-3-[2-(2-azidoethoxy)ethoxy]pyrrolidine(INT-Y4) as a light brown oil.

Step E: To a 250-mL round-bottom flask was added amine INT-Y4 (702 mg,3.5 mmol, 1 equiv), CH₂Cl₂ (50 mL), 4-(benzyloxy)benzene-1-sulfonylchloride (INT-L3 with R¹═H, 1 g, 3.5 mmol, 1 equiv), and triethylamine(2.8 mL). The resulting solution was stirred for 30 min at roomtemperature. The resulting solution was diluted with water and extractedwith 3×200 mL of CH₂Cl₂. The combined organic layers were washed with2×200 mL of brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with petroleum ether/ethyl acetate (3:1) providing 380 mg (24%)of(3R)-3-[2-(2-azidoethoxy)ethoxy]-1-[[4-(benzyloxy)benzene]sulfonyl]pyrrolidine(INT-Y5) as a light yellow oil.

Step F: To a 250-mL round-bottom flask purged and maintained with aninert atmosphere of H₂ was added azide INT-Y5 (700 mg, 1.57 mmol, 1equiv), methanol (40 mL), and palladium on carbon (200 mg). Theresulting slurry was stirred overnight at room temperature. Theresulting solution was diluted with 200 mL of methanol, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with CH₂Cl₂:methanol:triethylamine (100:10:1) providing 380 mg(73%) of4-[(3R)-3-[2-(2-aminoethoxy)ethoxy]pyrrolidine-1-sulfonyl]phenol(INT-Y6) as a light brown oil.

Step G: To a 250-mL round-bottom flask was added amine INT-Y6 (380 mg,1.15 mmol, 1 equiv), methanol (30 mL), and ethyl 2,2,2-trifluoroacetate(817.6 mg, 6.48 mmol, 5.6 equiv). The resulting solution was stirredovernight at room temperature. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withpetroleum ether/ethyl acetate (1:2). This resulted in 390 mg (80%) of2,2,2-trifluoro-N-[2-(2-[[(3R)-1-[(4-hydroxybenzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]acetamide(INT-Y7) as a light brown oil.

Other cyclic amine intermediates were generated from the analogousprocedure beginning with the appropriate Boc-aminoalcohol startingmaterials.

Representative Scheme for Synthesis of Cyclic-Substituted DimerProducts: Example 93:3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Step A: To a 250-mL round-bottom flask was added phenol INT-Y7 (390 mg,0.91 mmol, 1 equiv), tetrahydrofuran (20 mL), and aminoindanol INT-18F(369 mg, 0.92 mmol, 1 equiv). This was followed by the addition of PPh₃(480 mg, 1.83 mmol, 2 equiv) in several portions at 0° C. andsubsequently DIAD (370 mg, 1.83 mmol, 2 equiv) dropwise at 0° C. Theresulting solution was stirred for 40 min at room temperature. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with CH₂Cl₂:methanol:triethylamine (100:10:1)providing 2 g of tert-butylN-[(3R)-1-[(1S,2S)-4,6-dichloro-1-[4-[(3R)-3-[2-[2-(trifluoroacetamido)ethoxy]ethoxy(pyrrolidine-1-sulfonyl]phenoxy]-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-Y10) as a dark oil.

Step B: To a 250-mL round-bottom flask was added INT-Y10 (2 g, 2.47mmol, 1 equiv) and methanol (60 mL). This was followed by the additionof sodium hydroxide (3M_((aq)),10 mL). The resulting solution wasstirred for 1 h at 60° C. The resulting solution was extracted with2×200 mL of CH₂Cl₂. The combined organic layers were washed with 1×150ml, of brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (150:120) providing 370 mg(21%) of tert-butylN-[(3R)-1-[(1S,2S)-1-[4-[(3R)-3-[2-(2-aminoethoxy)ethoxy]pyrrolidine-1-sulfonyl]phenoxy]-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-Y11) as a light brown oil.

Step C: To a 100-mL round-bottom flask was added amine INT-Y11 (370 mg,0.52 mmol, 1 equiv), DMF (15 mL), and 1,4-diisocyanatobutane (36.3 mg,0.26 mmol, 0.5 equiv). The resulting solution was stirred for 1 h at 60°C. The resulting mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column with CH₂Cl₂:methanol:triethylamine(100:10:1). This resulted in 210 mg (26%) of tert-butylN-[(3R)-1-[(1S,2S)-1-[4-[(3R)-3-[2-[2-([[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-[[(tert-butoxy)carbonyl]amino]piperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)ethoxy]ethoxy]pyrrolidine-1-sulfonyl]phenoxy]-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl](carbamate(INT-Y12) as an off-white solid.

Step D: To a 100-mL round-bottom flask was added dimer INT-Y12 (210 mg,0.13 mmol, 1 equiv), CH₂Cl₂ (10 mL), and trifluoroacetic acid (1.5 mL).The resulting solution was stirred for 1 h at room temperature. The pHvalue of the solution was adjusted to 12 with saturated aqueouspotassium carbonate and extracted with 2×200 mL of CH₂Cl₂. The combinedorganic layers were washed with 1×200 mL of brine and concentrated undervacuum to provide crude compound Example 93.

Example 93:3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Crude product of Steps A-D was purified by preparative HPLC with thefollowing conditions: Column, XBridge Shield RP18 OBD Column, 19*150 mm,5 um; mobile phase, water (0.05% TFA) and CH₃CN (28.0% CH₃CN up to 39.0%in 10 min); Detector, UV 254 nm. This resulted in 81.4 g (38%) of thetitle compound as an off-white solid. MS (m/z): ¹H NMR (Methanol-d4, 400MHz) δ 7.86 (d, J=8.8 Hz, 4H), 7.45 (s, 2H), 7.34 (d, J=8.8 Hz, 4H),7.15 (s, 2H), 6.14 (d, J=5.6 Hz, 2H), 4.06 (s, 2H), 3.88-3.84 (m, 2H),3.50-3.40 (m, 16H), 3.40-3.37 (m, 6H), 3.29-3.22 (m, 7H), 3.09-3.03 (m,8H), 2.86 (s, 2H), 2.75-2.67 (m, 4H), 1.99-1.87 (m, 8H), 1.79-1.68 (m,2H), 1.64-1.62 (m, 2H), 1.60 (s, 4H), 1.29 (s, 1H).

Example 94:3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Beginning with INT-18F and INT-Y8, the crude product of Steps A-D waspurified by preparative HPLC with the following conditions: Column,XBridge C18 OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water(0.05% TFA) and CH₃CN (30.0% CH₃CN up to 36.0% in 9 min); Detector, UV220 nm. This resulted in 22 mg (13%) of the title compound as a brownsolid. MS (m/z): 1368 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz): δ 7.87 (d,J=8.8 Hz, 5H), 7.46 (s, 2H), 7.35 (d, J=8.8 Hz, 5H), 7.20 (s, 2H), 6.03(d, J=7.8 Hz, 2H), 4.08 (s, 2H), 3.70 (s, 2H), 3.55 (s, 3H), 3.51-3.49(m, 11H), 3.49-3.35 (m, 8H), 3.19-2.91 (m, 10H), 2.90 -2.80 (m, 2H),2.70-2.61 (m, 7H), 1.95-1.80 (m, 8H), 1.70-1.48 (m, 5H) 1.40 (s, 4H),1.32 (s, 2H).

Example 95:3-[2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]piperidin-4-yl]oxy)ethoxy]ethyl]-1[4-[([2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]piperidin-4-yl]oxy)ethoxy]ethyl]carbamoyl)amino]butyl]urea

Beginning with INT-18F and INT-Y9, the crude product of Steps A-D waspurified by preparative HPLC with the following conditions: Column,XBridge Shield RP18 OBD Column, Sum, 19*150 mm, 5 um; mobile phase,water (0.05% TFA) and CH₃CN (29.0% CH₃CN up to 36.0% in 13 min);Detector, UV 254 nm. This resulted in 112.8 mg (28%) of the titlecompound as an off-white solid. MS (m/z): 1395.4 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz): δ 7.80 (d, J=6.8 Hz, 4H), 7.44 (s, 2H), 7.34 (d,J=8.8 Hz, 4H), 7.17 (s, 2H), 6.04 (d, J=5.2 Hz, 2H), 3.75-3.72 (m, 2H),3.69 (s, 8H), 3.55-3.35 (m, 6H), 3.31-3.21 (m, 11H), 3.13-3.01 (m, 6H),2.99-2.72 (m, 7H), 2.71 (s, 2H), 2.65-2.60 (m, 6H), 1.93-1.84 (m, 8H),1.70-1.46 (m, 8H), 1.29 (s, 4H).

Representative Scheme for Synthesis of α-Alkyl-substituted SulfonamideLinkers:

Step A: To a 250-mL round-bottom flask, was added(2S)-2-aminopropan-1-ol (2.1 g, 28 mmol, 4 equiv) and CH₂Cl₂ (50 mL).This was followed by the dropwise addition of a solution of4-(benzyloxy)benzene-1-sulfonyl chloride (INT-L3 with R¹═H, 2 g, 7.07mmol, 1 equiv) in CH₂Cl₂ (50 mL). The resulting solution was stirred for40 min at room temperature. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate (100%) providing 2.33 g of(S)-4-(benzyloxy)-N-(1-hydroxypropan-2-yl)benzenesulfonamide (INT-B1) asa white solid.

Step B: To a 250-mL round-bottom flask, was added alcohol INT-B1 (960mg, 3 mmol, 1 equiv), azidotosylate INT-Y2 (870 mg, 3 mmol, 1 equiv),DMF (40 mL), and lastly sodium hydride (360 mg, 15.00 mmol, 5 equiv) inportions. The resulting slurry was stirred overnight at roomtemperature. The reaction was quenched by the addition of 100 mL ofwater and extracted with 3×150 mL of ethyl acetate. The combined organiclayers were dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:1) providing 300 mg (23%)ofN-[(2S)-1-[2-(2-azidoethoxy)ethoxy]propan-2-yl]-4-(benzyloxy)benzene-1-sulfonamide(INT-B2) as a yellow oil.)

Step C: To a 250-mL round-bottom flask was added azide INT-B2 (200 mg,0.46 mmol, 1 equiv), methanol (20 mL), and palladium on carbon (100 mg).Hydrogen gas was introduced into the flask. The resulting slurry wasstirred for 3 h at room temperature. The solids were removed byfiltration and the filtrate concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate (100%) providing 100mg (68%) ofN-[(2S)-1-[2-(2-aminoethoxy)ethoxy]propan-2-yl]-4-hydroxybenzene-1-sulfonamide(INT-B3) as a colorless oil.

Step D: To a 250-mL round-bottom flask, was added amine INT-B3 (400 mg,1.26 mmol, 1 equiv), methanol (35 mL), and ethyl 2,2,2-trifluoroacetate(892 mg). The resulting solution was stirred for 30 min at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (1:2) providing 430 mg (83%) of(S)-2,2,2-trifluoro-N-(2-[2-(2-[(4-hydroxyphenyl)sulfonamide]propoxy)ethoxy]ethyl)acetamide(INT-B4) as a light yellow oil.

Other α-alkyl-substituted sulfonamide intermediates were generated fromthe analogous procedure beginning with the appropriate aminoalcoholstarting materials.

The germinal dimethyl version of these α-alkyl-substituted sulfonamidelinkers was made through the following procedure.

Step A: To a 100-mi, 3-necked round-bottom flask purged and maintainedwith an inert atmosphere of nitrogen was added methyl3-hydroxy-2,2-dimethylpropanoate (1.32 g, 10 mmol, 1 equiv), CH₂Cl₂ (40mL), and 2,6-lutidine (1.6 g, 15 mmol, 1.5 equiv). This was followed bythe dropwise addition of triflic anhydride (Tf₂O, 3.39 g, 12 mmol, 1.2equiv) −78° C. The resulting solution was stirred for 15 min at −78° C.and then gradually warmed to room temperature over 3 h. The resultingsolution was diluted with 100 mL of ethyl acetate and sequentiallywashed with 1×50 mL of water, 2×40 mL of 2M hydrogen chloride, and 2×40mL of brine. The mixture was dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. This resulted in 2.64 g (100%crude) of methyl2,2-dimethyl-3-[(trifluoromethane)sulfonyloxy]propanoate INT-B8 as abrown oil.

Step B: To a 100-mL round-bottom flask was added triflate INT-B8 (2.64g, 10 mmol, 2 equiv), 2-(2-azidoethoxy)ethan-1-ol (INT-Y2, 650 mg, 5mmol, 1 equiv), and DMF (40 mL). This was followed by the addition ofsodium hydride (60% in oil, 400 mg, 10 mmol, 2 equiv) in portions at 0°C. The resulting slurry was stirred for 14 h at room temperature. Thereaction was quenched by the slow addition of 100 mL of water andextracted with 3×50 mL of ethyl acetate. The combined organic layerswere washed with 1×100 mL of water and 1×100 mL of brine, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Thisresulted in 1.23 g (100% crude) of methyl3-[2-(2-azidoethoxy)ethoxy]-2,2-dimethylpropanoate (INT-B9) as a brownoil.

Step C: To a 100-mL round-bottom flask was added ester INT-B9 (3.68 g,15 mmol, 1 equiv), tetrahydrofuran (30 mL), and water (20 mL). This wasfollowed by the addition of LiOH—H₂O (1.26 g, 30 mmol, 2 equiv) inportions at room temperature. The resulting solution was stirred for 4 hat 50° C. The reaction mixture was cooled to room temperature anddiluted with of water. The volatiles were removed under vacuum and theresulting mixture washed with 2×30 mL of petroleum ether. The pH of theaqueous layer was adjusted to 1-2 with 3M aqueous hydrogen chloride andextracted with 3×40 mL of CH₂Cl₂. The combined organic layers werewashed with 1×50 mL of water and 1×50 mL of brine, dried over anhydroussodium sulfate, filtered, and concentrated under vacuum. This resultedin 2.4 g (69% crude) of3-[2-(2-azidoethoxy)ethoxy]-2,2-dimethylpropanoic acid (INT-B10) as alight yellow oil.

Step D: To a 100-mL round-bottom flask was added carboxylic acid INT-B10(2.4 g, 10.4 mmol, 1 equiv), toluene (30 mL), and triethylamine (2.1 g,20.8 mmol, 2 equiv). This was followed by the dropwise addition of DPPA(4.1 g, 14.9 mmol, 1.5 equiv) with stirring at room temperature. Theresulting solution was stirred for 1 h at room temperature. Water (10mL) was added and the resulting slurry allowed to react with stirringfor an additional 14 h at reflux. The resulting solution was dilutedwith 40 mL of water and hydrogen chloride (3M_((aq)), 20 mL). Theresulting mixture was washed with 1×50 mL of petroleum ether. The pHvalue of the aqueous layer was adjusted to 13-14 with sodium hydroxideand extracted with 3×50 mL of CH₂Cl₂. The combined organic layers werewashed with 1×50 mL of water and 1×50 mL of brine, dried over anhydroussodium sulfate, filtered, and concentrated under vacuum. This resultedin 1.5 g (71% crude) of1-(2-amino-2-methylpropoxy)-2-(2-azidoethoxy)ethane (INT-B11) as a lightyellow oil.

Step E: To a 100-mL round-bottom flask was amine INT-B11 (1.5 g, 7.42mmol, 1.5 equiv), CH₂Cl₂ (40 mL), and triethylamine (1.5 g, 14.8 mmol, 2equiv). This was followed by the addition of4-(benzyloxy)benzene-1-sulfonyl chloride (INT-L3 with R¹═H, 1.41 g, 5mmol, 1 equiv) in portions at room temperature. The resulting solutionwas stirred overnight at room temperature. The resulting solution wasdiluted with 200 mL of ethyl acetate and washed with 2×100 mL of waterand 1×100 mL of brine. The mixture was dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue wasapplied onto a silica gel column with petroleum ether/ethyl acetate(8:1-2:1) providing 1.8 g (80%) ofN-[1-[2-(2-azidoethoxy)ethoxy]-2-methylpropan-2-yl]-4-(benzyloxy)benzene-1-sulfonamide(INT-B12) as a light yellow oil.

Step F: To a 100-mL round-bottom flask was added azide INT-B12 (1.8 g,4.0 mmol, 1 equiv), methanol (40 mL), and palladium on carbon (180 mg,0.10 equiv). To the above, hydrogen (1 atm) was introduced in and theresulting slurry stirred overnight at room temperature. The solids werefiltered out. The resulting mixture was concentrated under vacuumproviding 1.33 g (100%) ofN-[1-[2-(2-aminoethoxy)ethoxy]-2-methylpropan-2-yl]-4-hydroxybenzene-1-sulfonamide(INT-B13) as a colorless oil.

Step G: To a 100-mL round-bottom flask was added amine INT-B13 (1.33 g,4.0 mmol, 1 equiv) and CH₂Cl₂ (40 Ml) followed by the dropwise additionof ethyl 2,2,2-trifluoroacetate (2.84 g, 20 mmol, 5 equiv) at roomtemperature. To this was added triethylamine (40 mg, 0.40 mmol, 0.1equiv). The resulting solution was stirred for 1 h at room temperature.The resulting mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column with petroleum ether/ethyl acetate(4:1-2:1) providing 1.57 g (92%) of2,2,2-trifluoro-N-[2-(2-[2-[(4-hydroxybenzene)sulfonamido]-2-methylpropoxy]ethoxy)ethyl]acetamide(INT-B14) as a light yellow oil.

Representative Scheme for Synthesis of α-Alkyl-substituted DimerProducts: Example 96:1-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-3-(4-[[(2-[2[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea;hydrochloride

Step A: To a 100-mL round-bottom flask was added phenol INT-B4 (430 mg,1.04 mmol, 1 equiv), tetrahydrofuran (25 mL), aminoindanol INT-18F (416mg, 1.04 mmol, 1 equiv), and PPh₃ (408 mg, 1.56 mmol, 1.5 equiv). Thiswas followed by the dropwise addition of a solution of DIAD (314 mg,1.55 mmol, 1.5 equiv) in tetrahydrofuran (2 mL) over 20 min. Theresulting solution was stirred for 40 min at 40° C. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate (100%) providing 1 g of tert-butylN-[(3R)-1-[(1S,2S)-4,6-dichloro-1-(4-[[(2S)-1-[2-[2-(trifluoroacetamido)ethoxy]ethoxy]propan-2-yl]sulfamoyl]phenoxy)-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-B15) as a brown oil.

Step B: To a 250-ml, round-bottom flask was added INT-B15 (1 g, 1.25mmol, 1 equiv) and methanol (50 mL) followed by the addition of sodiumhydroxide (3M_((aq)), 8 mL). The resulting solution was stirred for 45min at 60° C. The resulting slurry was extracted with 3×150 mL ofCH₂Cl₂. The combined organic layers were dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. This resulted in 230mg (26%) of tert-butylN-[(3R)-1-[(1S,2S)-1-(4-[[(2S)-1-[2-(2-aminoethoxy)ethoxy]propan-2-yl]sulfamoyl]phenoxy)-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-B16) as a light yellow solid.

Step C: To a 100-mL round-bottom flask was added amine monomer INT-B16(230 mg, 0.33 mmol, 1 equiv), DMF (20 mL), and 1,4-diisocyanatobutane(23 mg, 0.16 mmol, 0.5 equiv). The resulting solution was stirred for 1h at 60° C. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with CH₂Cl₂/methanol (10:1)providing 150 mg (30%) of tert-butylN-[(3R)-1-[(1S,2S)-1-(4-[[(2S)-1-[2-(2-[[(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-[[(tert-butoxy)carbonyl]amino]piperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)carbamoyl]amino]butyl)carbamoyl]amino]ethoxy)ethoxy]propan-2-yl]sulfamoyl]phenoxy)-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-B17) as a light brown solid.

Step D: To a 100-mL round-bottom flask was added Boc-dimer B17 (150 mg,0.10 mmol, 1 equiv), CH₂Cl₂ (10 mL), and trifluoroacetic acid (1.5 mL).The resulting solution was stirred for 1 h at room temperature. The pHvalue of the solution was adjusted to 12 with saturated aqueouspotassium carbonate and extracted with 100 mL of CH₂Cl₂. The organiclayer was washed with 2×100 mL of brine, dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum to provide crudecompound Example 96.

Example 96:1-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-3-(4-[[(2-[2-[(2S-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea;hydrochloride

Crude product of Steps A-D was purified by preparative HPLC with thefollowing conditions: Column, XBridge Preparative C18 OBD Column, 19*150mm, 5 um; mobile phase, water (0.05% HCl) and CH₃CN (25.0% CH₃CN up to55.0% in 10 min); Detector, UV 254 nm. This resulted in 20.8 mg (16%) ofthe title compound as a light yellow solid. MS (m/z): 1343.7 [M+H]⁺. ¹HNMR (Methanol-d4, 400 MHz) δ 7.96 (d, J=8.8 Hz, 4H), 7.52 (s, 2H), 7.40(d, J=8.8 Hz, 4H), 7.04 (s, 2H), 6.78 (d, J=4.0 Hz, 2H), 4.60-4.42 (m,2H), 3.90-3.66 (n, 8H), 3.55-3.49 (n, 18H), 3.32-3.10 (m, 10H), 3.09 (s,4H), 2.28-2.00 (m, 6H), 1.78-1.66 (m, 2H), 1.46 (s, 4H), 1.30-1.28 (m,1H), 1.07 (d, J=6.4 Hz, 6H).

Example 97:3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-1-(4-[[2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea

Beginning with INT-I8F and INT-B5, the crude product of Steps A-D waspurified by preparative HPLC with the following conditions: Column,XBridge C18 OBD Preparative Column, 19*250 mm, 5 um; mobile phase,waters (0.05% TEA) and CH₃CN (17.0% CH₃CN up to 60.0% in 8 min);Detector, UV 254 nm. This resulted in 150.7 mg (43%) of the titlecompound as a white solid. MS (m/z): 1343.25 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.96-7.86 (m, 4H), 7.45 (d, J=1.6 Hz, 2H), 7.30(d, J=8.8 Hz, 4H), 7.12 (s, 2H), 6.20 (d, J=5.6 Hz, 2H), 3.92-3.78 (m,2H), 3.56-3.50 (m, 12H), 3.50-3.30 (m, 8H), 3.29-3.26 (m, 6H), 3.13-3.04(m, 8H), 3.04-2.82 (m, 2H), 2.78-2.73 (m, 4H), 1.96-1.88 (m, 4H),1.63-1.61 (m, 2H), 1.61-1.55 (m, 2H), 1.44 (s, 4H), 1.06 (d, J=6.4 Hz,6H).

Example 98:3-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy])benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]amino]butyl)ureadihydrochloride

Beginning with INT-I8F and INT-B6, the crude product of Steps A-D waspurified by preparative HPLC with the following conditions: Column,XBridge Preparative C18 OBD Column, 19*150 mm, 5 um; mobile phase, water(0.05% HCl) and CH₃CN (40.0% CH₃CN up to 60.0% in 10 min); Detector, UV254 nm. This resulted in 82.8 mg (18%) of the title compound as a whitesolid. MS (m/z): 1400 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ 7.98 (d,J=8.4 Hz, 4H), 7.55 (s, 2H), 7.42 (d, J=8.4 Hz, 4H), 7.05 (s, 2H), 6.86(d, J=6.4 Hz, 2H), 4.57 (q, J=8.0 Hz, 2H), 3.84-3.71 (m, 8H), 3.59-3.27(m, 24H), 3.22 (q, J=5.4 Hz, 2H), 3.12 (s, 4H), 2.33-2.19 (m, 6H),1.97-1.69 (m, 4H), 1.50 (s, 4H), 0.90 (t, J=6.4 Hz, 12H).

Example 99:3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea

Beginning with INT-I8F and INT-B7, the crude product of Steps A-D waspurified by preparative HPLC with the following conditions: Column,XBridge Shield RP18 OBD Column, 19*150 mm, 5 um; mobile phase, water(0.05% TFA) and CH₃CN (30.0% CH₃CN up to 47.0% in 8 min); Detector, UV254 nm. This resulted in 48.6 mg (56%) of the title compound as a whitesolid. MS (m/z): 1400 [M+H]⁺. ¹H NMR (Methanol-d4, 400 MHz): δ 7.95-7.87(d, J=9.2 Hz, 4H), 7.46 (d, J=1.6 Hz, 2H), 7.30 (d, J=6.4 Hz, 4H), 7.14(s, 2H), 6.15 (d, J=8.8 Hz, 2H), 3.80 (q, J=5.6 Hz, 2H), 3.56-3.34 (m,18H), 3.34-3.26 (m, 4H), 3.22-3.18 (m, 2H), 3.13-2.99 (m, 8H), 2.83 (s,2H), 2.78-2.66 (m, 4H), 2.03-1.82 (m, 6H), 1.79-1.57 (m, 4H), 1.46 (s,4H), 0.89 (t, J=6.4 Hz, 12H).

Example 100:1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-2-methylpropoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-2-methylpropoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;hydrochloride

Beginning with INT-I8F and INT-B14, the crude product of Steps A-D waspurified by preparative HPLC with the following conditions: Column,XBridge Preparative C18 OBD Column, 19*150 mm, 5 um; mobile phase, water(0.05% HCl) and CH₃CN (30% CH₃CN up to 60% in 10 min); Detector, UV 254nm. This resulted in 217.6 mg (45%) of the title compound as a lightyellow solid. MS (m/z): 1371.25 [M+H]⁺. ¹H NMR (Methanol-d₄, 400 MHz) δ7.99 (d, =8.8 Hz, 4H), 7.54 (s, 2H), 7.42 (d, J=8.8 Hz, 4H), 7.05 (s,2H), 6.85 (d, J=6.0 Hz, 2H), 4.55 (q, J=7.8 Hz, 2H), 3.92-3.73 (m, 8H),3.64-3.56 (m, 12H), 3.47 (q, J=8.2 Hz, 2H), 3.42-3.29 (m, 14H), 3.10 (s,4H), 2.26-2.12 (m, 6H), 1.85-1.70 (m, 2H), 1.48 (s, 4H), 1.23 (s, 12H).

General Scheme for Synthesis of Ortho-Substituted Sulfonamide DimerProducts:

Step A: To a round-bottom flask was added aminoindanol INT-I8F (1 equiv)and tetrahydrofuran (0.2M), followed by the addition of phenol linkerINT-L6 (1.1 equiv) and heating to 40° C. To this slurry was added PPh₃(2 equiv) and DIAD (1.5 equiv). The resulting solution was stirred for1-3 h at 40° C. The resulting mixture was concentrated under vacuum anddiluted with CH₂Cl₂. The residue was applied onto a silica gel columnwith petroleum ether/ethyl acetate (1:1) providing indane monomerINT-E1.

Step B: To a round-bottom flask was added indane monomer INT-E1 (1equiv), methanol (0.1M), and sodium hydroxide (3M_((aq)), 3-5 equiv).The resulting solution was stirred for 1-2 h at 60° C. The resultingmixture was concentrated under vacuum and diluted with CH₂Cl₂. Theresidue was applied onto a silica gel column with CH₂Cl₂/methanol (10:1)providing indane amine monomer INT-D2.

Step C: To a round-bottom flask was added INT-E2 (1 equiv),N,N-dimethylformamide (DMF, 0.1M), and 1,4-diisocyanatobutane (0.4-0.5equiv). The resulting solution was stirred for 2 h at 60° C. Theresulting mixture was concentrated under vacuum and diluted with ofCH₂Cl₂. The residue was applied onto a silica gel column withchloroform/methanol (10:1) providing the desired dimer of structure (I).Final products were purified by preparative HPLC. The final productswere generally isolated as the free based amines, TFA salts, orhydrochloride salts.

Step D: To a round-bottom flask was added Boc-protected dimer (I) (1equiv) and 5:1 CH₂Cl₂:TFA (˜0.05M). The resulting solution was stirredfor 2 h at room temperature. The resulting mixture was concentratedunder vacuum. The crude product was purified by preparative HPLC. Thefinal products were generally isolated as the free based amines, TFAsalts, or hydrochloride salts.

Example 101:1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Beginning with INT-L6J and INT-I8F, Steps A-D provided Example 101 whichwas purified by preparative HPLC with the following conditions: Column,XBridge Shield RP18 OBD Column, 19*150 mm, 5 um; mobile phase, water(0.05% TFA) and CH₃CN (15.0% CH₃CN up to 50.0% in 8 min); Detector, UV254 nm. This resulted in 0.146 g (100%) of the title compound as a whitesolid. MS (m/z): 1375.80 [M+H]⁺. ¹H NMR (Methanol-d4,400 MHz): δ 7.83(d, J=8.8 Hz, 2H), 7.44 (s, 2E1), 7.18 (s, 2H), 6.93-6.86 (m, 4H), 6.05(s, 2H), 3.96 (s, 6H), 3.70 (s, 2H), 3.60-3.53 (m, 9H), 3.51-3.48 (m,9H), 3.40-3.31 (m, 8H), 3.12-3.09 (m, 6H), 3.03 (t, J=5.41-1z, 6H), 2.71(d, J=8.0 Hz, 2H), 2.62-2.58 (m, 4H), 1.96-1.91 (m, 2H), 1.84 (s, 2H),1.80-1.68 (m, 2H), 1.65-1.50 (m, 2H), 1.46 (s, 4H).

Example 102:3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Beginning with INT-L6K and INT-18F, Steps A-D provided Example 102 whichwas purified by preparative HPLC with the following conditions: Column,XSelect CSH Preparative C18 OBD Column, 19*150 mm, 5 um; mobile phase,water (0.05% TFA) and CH₃CN (25.0% CH₃CN up to 37.0% in 10 min);Detector, UV 254 nm. This resulted in 30.4 mg (20%) of the titlecompound as a solid. MS (m/z): 1343.4 [M+H]⁺. ¹H NMR (Methanol-d4, 400MHz) δ 7.95 (d, J=8.8 Hz, 2H), 7.46 (s, 2H), 7.19-7.11 (m, 6H), 6.12 (d,J=5.8 Hz, 2H), 3.78 (q, J=7.4 Hz, 2H), 3.63-3.45 (m, 17H), 3.41-3.35 (m,2H), 3.35-3.25 (m, 8H), 3.13-3.05 (m, 8H), 3.05-2.98 (m, 4H), 2.85 (s,2H), 2.70-2.60 (m, 9H), 2.00-1.85 (m, 4H), 1.73 (d, J=9.0 Hz, 2H), 1.59(d, J=8.8 Hz, 2H), 1.46 (s, 4H), 1.33 (t, J=8.8 Hz, 2H).

Example 103:1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea

Beginning with INT-L6L and INT-I8F, Steps A-D provided Example 103 whichwas purified by preparative HPLC with the following conditions: Column,XSelect CSH Preparative C18 OBD Column, 19*150 mm, 5 um; mobile phase,water (0.05% TFA) and CH₃CN (23.0% CH₃CN up to 41.0% in 8 min);Detector, UV 254 nm. This resulted in 53.2 mg (69%) of the titlecompound as a white solid. MS (m/z): 1351.75 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.88 (t, J=8.6 Hz, 2H), 7.47 (d, J=1.8 Hz, 2H),7.23-7.10 (m, 6H), 6.11 (d, J=16.4 Hz, 2H), 3.76 (s, 2H), 3.63-3.49 (m,16H), 3.42-3.36 (m, 4H), 3.36-3.29 (m, 6H), 3.29-3.20 (m, 4H), 3.20-3.10(m, 4H), 3.10-2.96 (m, 4H), 2.96-2.56 (m, 6H), 1.94 (d, J=32.2 Hz, 4H),1.66 (d, J=46.6 Hz, 4H), 1.49 (s, 4H).

Scheme for Synthesis of Example 104: Example 104:4-([(1S,2S)-2-[(R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-2-[(R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy)-2-chlorophenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacasyl]-2-chlorobenzenesulfonamide;bis(trifluroacetic acid)

Step A: To a round-bottom flask was added aminoindanol INT-18F (0.602 g,1.5 mmol, 1 equiv) and tetrahydrofuran (3.5 mL), followed by theaddition of 4-bromo-3-chlorophenol (0.374 g, 1.8 mmol, 1.2 equiv) andheating to 45° C. To this slurry was added PPh3 (0.590 g, 2.25 mmol, 1.5equiv) followed DIAD (0.443 mL, 2.25 mmol, 1.5 equiv) dropwise. Theresulting solution was stirred for 3 h at 40° C. The resulting mixturewas concentrated under vacuum and diluted with CH₂Cl₂. The residue wasapplied onto a silica gel column with hexanes/ethyl acetate (0-50%)providing 0.886 g (99%) of tert-butyl[(R)-1-[(1S,2S)-1-(4-bromo-3-chlorophenoxy)-4,6-dichloro-2,3-dihydro-1H-inden-2-yl)piperidin-3-yl]carbamate(INT-E3) as a pale pink foam.

Step B: To a round-bottom flask purged and maintained with an inertatmosphere of nitrogen was added arylbromide INT-E3 (0.870 g, 1.47 mmol,1 equiv), 1,4-dioxane (7.4 mL), N,N-diisopropylethylamine (0.381 g, 2.95mmol, 2 equiv), Pd₂(dba)₃.CHCl₃ (33.7 mg, 0.037 mmol, 0.025 equiv), andXantphos (38.9 mg, 0.067 mmol, 0.05 equiv). The solution was degassedwith nitrogen bubbling for 5 min before the addition of benzylmercaptan(0.219 g, 1.76 mmol, 1.2 equiv) in one portion. The resulting solutionwas stirred overnight at 90° C. The resulting slurry was concentratedunder vacuum. The residue was applied onto a silica gel column withhexanes/acetone (0-20%) providing 0.607 g (65%) of tert-butyl[(R)-1-[(1S,2S)-1-(4-(benzylthio)-3-chlorophenoxy)-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-E4) as a light orange solid.

Step C: To a round-bottom flask was added thioether INT-E4 (0.607 g,0.95 mmol, 1 equiv), acetic acid (3 mL), and water (1 mL). This wasfollowed by the addition of N-chlorosuccinimide (0.384, 2.87 mmol, 3equiv) in several batches at room temperature. The resulting solutionwas stirred for 2 h at room temperature. The resulting slurry wasdiluted with 50 mL of ethyl acetate and treated with 4.6 g of sodiumbicarbonate. Water (50 mL) was added and the layers separated. Theorganic layer was washed with 1×50 mL saturated aqueous sodiumbicarbonate and 1×50 mL brine. The organic layer was dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Thisprovided 740 mg of crude tert-butyl[(R)-1-[(1S,2S)-4,6-dichloro-1-[3-chloro-4-(chlorosulfonyl)phenoxy]-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-E5) as a pasty solid that was used without further purification.

Step D: To a round-bottom flask was added crude sulfonyl chloride INT-E5(theoretical 0.95 mmol) from Step C and CH₂Cl₂ (1 mL). To this mixturewas added 2,2′-(ethane-1,2-diylbis(oxy))bis(ethan-1-amine) (1.04 g, 7mmol, 7 equiv) dropwise over 2 min. The reaction solution was stirredovernight at room temperature. The reaction slurry was diluted with 15mL of CH₂Cl₂ and 10 mL of ethyl acetate. The organic layer was washedwith 3×30 mL of water and 2×30 mL of brine. The resulting mixture wasconcentrated under vacuum and diluted with of CH₂Cl₂. The residue wasapplied onto a silica gel column with CH₂Cl₂/methanol (0-15%) providing0.335 g (49% over 2 steps) of tert-butyl[(R)-1-[(1S,2S)-1-(4-[N-(2-[2-(2-aminoethoxy)ethoxy]ethyl)sulfamoyl]-3-chlorophenoxy)-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate(INT-E6) as a white foam.

Step E: To a round-bottom flask was added INT-E6 (0.181 g, 0.25 mmol, 1equiv), DMF (5 mL), and 1,4-diisocyanatobutane (15.8 mg, 0.113 mmol,0.45 equiv). The resulting solution was stirred for 4 h at roomtemperature. The resulting mixture was concentrated under vacuum andused directly in Step F.

Step F: The crude material from Step E (theoretical 0.113 mmol) wasdiluted in 3:1 CH₂Cl₂:TFA (4 mL). The resulting solution was stirred for1 h at room temperature. The resulting mixture was concentrated undervacuum. The crude product was purified by preparative HPLC.

Steps A-F provided Example 104 which was purified by Preparative HPLCwith the following conditions: Column, Atlantis T3 OBD Column, 19*150mm, 10 um; mobile phase, water (0.1% TFA) and CH₃CN (0.1% TFA, 20% CH₃CNup to 70.0% in 40 min); Detector, UV 254 nm. This resulted in 0.174 g(100%) of the title compound as a white solid. MS (m/z): 1383 [M+H]⁺. ¹HNMR (Methanol-d₄, 400 MHz): δ 8.06 (d, J=8.9 Hz, 2H), 7.48-7.40 (m, 4H),7.27 (dd, J=8.9, 1.8 Hz, 2H), 7.16 (s, 2H), 6.20 (d, J=5.4 Hz, 2H), 3.89(dd, J=13.4, 7.3 Hz, 2H), 3.74-3.43 (m, 19H), 3.43-3.28 (m, 15H),3.20-3.10 (m, 16H), 2.95 (s, 2H), 2.84-2.58 (m, 4H), 2.00 (s, 2H), 1.92(s, 2H), 1.77 (d, J=9.6 Hz, 1H), 1.74-1.30 (m, 7H).

Representative Scheme for the Synthesis of Linker Amine Dimers:

Step A: To a 500-mL round-bottom flask was added tert-butylN-[(3R)-pyrrolidin-3-yl]carbamate (10 g, 53.7 mmol, 1 equiv),1-[[2-(2-azidoethoxy)ethoxy]sulfonyl]-4-methylbenzene (INT-Y2, 16.85 g,59.1 mmol, 1.1 equiv), CH₃CN (100 mL), and potassium carbonate (22.26 g,161 mmol, 3 equiv). The resulting solution was stirred overnight at 60°C. The solids were filtered out and the resulting mixture wasconcentrated under vacuum providing 13 g (81%) of tert-butylN-[(3R)-1-[2-(2-azidoethoxy)ethyl]pyrrolidin-3-yl]carbamate (INT-RD1) asa yellow oil.

Step B: To a 250-mL round-bottom flask flushed with N₂ was added ethanol(100 mL), Raney Ni (10 g), azide INT-RD1 (6 g, 20 mmol, 1 equiv), andNH₄OH (28%, 10 mL). To the above H_(2(g)) was introduced in followed bya purging/filling cycle, leaving the slurry under an atmosphere ofH_(2(g)). The resulting slurry was stirred for 2 h at room temperature.The solids were filtered out and the resulting mixture concentratedunder vacuum providing 4.8 g (88%) of tert-butylN-[(3R)-1-[2-(2-aminoethoxy)ethyl]pyrrolidin-3-yl]carbamate (INT-RD2) asa yellow oil.

Step C: To a 500-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added amine INT-RD2 (10 g, 36.6 mmol, 1equiv), DMF (250 mL), and 1,4-diisocyanatobutane (2.6 mL, 0.45 equiv).The resulting solution was stirred for 2 h at 60° C. The resultingslurry was concentrated under vacuum. The residue was applied onto asilica gel column with CH₃CN:H₂O (35:65) providing 9.0 g of tert-butylN-[(3R)-1-[2-(2-[[(4-[[(2-[2-[(3R)-3-[[(tert-butoxy)carbonyl]amino]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)carbamoyl]amino]ethoxy)ethyl]pyrrolidin-3-yl]carbamate(INT-RD3) as a white solid.

Step D:3-(2-[2-[(3R)-3-Aminopyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-aminopyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea hydrochloride. To a 250-mL round-bottom flask was addedBoc-diamine INT-RD3 (3.0 g, 4.37 mmol, 1 equiv), CH₂Cl₂ (15 mL), CH₃CN(15 mL), and hydrogen chloride (4M_((aq)), 15 mL). The resultingsolution was stirred for 2 h at room temperature. The resulting mixturewas concentrated under vacuum. This resulted in 2.2099 g (91%) of thetitle compound as a brown oil. MS (m/z): 487 [M+H]⁺. ¹H NMR(Methanol-d4, 300 MHz) δ 4.29-4.12 (m, 3H), 4.01-3.73 (m, 7H), 3.75-3.48(m, 10H), 3.40 (t, J=4.9 Hz, 6H), 3.19 (d, J=5.8 Hz, 4H), 2.70 (tt,J=24.7, 11.1 Hz, 2H), 2.30 (qd, J=8.0, 3.7 Hz, 2H), 1.60-1.49 (m, 4H).

Through Steps A-D, 2.2449 g (92%) of3-(2-[2-[(3S)-3-aminopyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-aminopyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)ureahydrochloride (INT-SD4) was prepared as a brown solid. MS (m/z): 487[M+H]⁺. ¹H NMR (Methanol-d4, 300 MHz) δ 4.26 (s, 2H), 4.18 (s, 1H), 3.98(d, J=12.5 Hz, 2H), 3.83 (t, J=4.5 Hz, 5H), 3.77-3.50 (m, 10H), 3.41 (t,J=5.2 Hz, 5H), 3.26-3.16 (m, 4H), 2.74 (s, 2H), 2.31 (ddd, J=13.8, 8.4,5.0 Hz, 2H), 1.62-1.51 (m, 4H).

Representative Scheme for the Synthesis of Thioether Indane Scaffolds:

Step A: To a 1000-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added 4-bromo-2-fluorophenol (20 g,104.7 mmol, 1 equiv), dioxane (240 mL), Xantphos (7.28 g, 12.6 mmol,0.12 equiv), diisopropylethylamine (34.6 mL), Pd₂(dba)₃.CHCl₃ (6.52 g),and benzylmercaptan (24.6 mL). The resulting solution was stirredovernight at 100° C. in an oil bath. The resulting mixture wasconcentrated under vacuum. The resulting residue was slurried in waterand extracted with 3×500 mL of ethyl acetate. The combined organiclayers were washed with 3×500 mL of brine, dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue wasapplied onto a silica gel column with hexane/ethyl acetate (0-10%)providing 14 g (57%) of 4-(benzylsulfonyl)-2-fluorophenol (INT-TE1) as ayellow solid.

Step B: To a 100-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added aminoindanol INT-18M (3 g, 6.95mmol, 1 equiv), tetrahydrofuran (16.2 mL), phenol INT-TE1 (1.71 g, 7.30mmol, 1.05 equiv), and PPh3 (2.92 g, 11.1 mmol, 1.6 equiv). This wasfollowed by the dropwise addition of DIAD (2.12 g, 10.5 mmol, 1.55equiv) at 40° C. over 45 min. The resulting solution was stirred for 1 hat 40° C. in an oil bath. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:40) providing 3.3 g (73%) of tert-butyl4-[(1S,2S)-1-[4-(benzylsulfanyl)-2-fluorophenoxy]-4-bromo-6-chloro-2,3-dihydro-1H-inden-2-yl]piperazine-1-carboxylate(INT-TE2) as a purple solid.

Step C: To a 100-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added arylbromide INT-TE2 (3.3 g, 5.09mmol, 1 equiv), NMP (33 mL), Zn(CN)₂ (312 mg, 0.52 equiv), and Pd(PPh₃)₄(589 mg, 0.10 equiv). The resulting solution was stirred overnight at100° C. in an oil bath. The resulting solution was diluted with waterand extracted with 3×30 mL of ethyl acetate. The combined organic layerswere washed with 3×30 mL of brine and concentrated under vacuum. Theresidue was applied onto a silica gel column with petroleum ether/ethylacetate (7:1) providing 2.05 g (68%) of tert-butyl4-[(1S,2S)-1-[14-(benzylsulfonyl)-2-fluorophenoxy]-6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl]piperazine-1-carboxylate(INT-TE3) as a gray solid. MS (m/z): 594 [M+H]⁺. ¹H NMR (Methanol-d4,300 MHz) δ 7.71 (d, J=2.0 Hz, 1H), 7.49-7.41 (m, 1H), 7.33-7.02 (m, 8H),5.80 (d, J=6.1 Hz, 1H), 4.07 (s, 2H) 3.70-3.56 (m, 1H), 3.34 (t, J=4.8Hz, 4H), 3.02 (dd, J=16.7, 7.8 Hz, 1H), 2.51 (qd, J=11.6, 5.3 Hz, 4H),1.42 (s, 9H).

Using INT-18C, Steps A and B provided crude INT-TE4. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:10) providing 3.2 g (62%) of (1S,2S)-1-[4-(benzylsulfonyl)-2-fluorophenoxy]-4,6-dichloro-N,N-dimethyl-2,3-dihydro-1H-inden-2-amine(INT-TE4) as a white solid. MS (m/z): 462 [M+H]⁺. ¹H NMR (Methanol-d4,400 MHz) δ 7.40 (d, J=1.7 Hz, 1H), 7.30-7.15 (m, 6H). 7.17-7.04 (m, 3H),5.78 (d, J=5.7 Hz, 1H), 4.09 (s, 2H), 3.46 (td, J=7.7, 5.8 Hz, 1H), 3.26(dd, J=16.6, 8.1 Hz, 1H), 2.85 (dd, J=16.6, 7.4 Hz, 1H), 2.31 (s, 6H).

Using INT-IBL, Steps A-C provided crude INT-TE5. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:10)providing 2.31 g (59%) of tert-butyl4-[(1S,2S)-1-[4-(benzylsulfanyl)-2-fluorophenoxy]-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperazine-1-carboxylate(INT-TE5) as a light purple solid. MS (m/z): 603 [M+H]⁺. ¹H NMR(DMSO-d6, 400 MHz) δ 7.57 (d, J=1.8 Hz, 1H), 7.45 (t, J=8.8 Hz, 1H),7.33-7.09 (m, 8H), 5.89 (d, J=5.6 Hz, 1H), 4.19 (s, 2H), 3.61-3.51 (m,1H), 3.30 (s, 4H), 3.08 (dd, J=16.7, 8.0 Hz, 1H), 2.83 (dd, J=16.7, 7.1Hz, 1H), 2.40 (dp, J=21.7, 5.6, 4.9 Hz, 4H), 1.36 (s, 911).

Using INT-18M and 4-bromophenol, Steps A-C provided crude INT-TE6. Theresidue was applied onto a silica gel column with petroleum ether/ethylacetate (10%) providing 2.05 g (79%) of tert-butyl4-[(1S,2S)-1-[4-(benzylsulfonyl)phenoxy]-6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl]piperazine-1-carboxylate(INT-TE6) as a gray solid. MS (m/z): 576 [M+H]⁺. ¹H NMR (Methanol-d4,300 MHz) δ 8.10-8.01 (m, 1. H), 7.46 (d, J=8.5 Hz, 1H), 3.94 (t, J=6.2Hz, 1H), 3.05 (t, J=6.9 Hz, 1H), 2.64 (d, J=13.8 Hz, 1H), 2.22 (d,J=11.8 Hz, 1H), 2.02 (s, 1H), 1.73 (q, J=13.3, 9.8 Hz, 3H), 1.43 (d,J=13.6 Hz, 3H), 1.33-1.11 (m, 2H), 0.86 (s, 1H).

Scheme for the Synthesis of Thioether INT-TE8

The thioether INT-TE8 was synthesized by reversing the steps from theprevious method as shown in the scheme above.

Step A: To a 100-mL 3-necked round-bottom flask purged and maintainedwith an inert atmosphere of nitrogen was added aminoindanol INT-19C (2.5g, 8 mmol, 1 equiv), 4-bromo-2-methylphenol (1.82 g, 9.73 mmol, 1.2equiv), tetrahydrofuran (19 mL), and PPh3 (3.2 g, 12.2 mmol, 1.5 equiv).This was followed by the dropwise addition of DIAD (2.4 mL) at 40-45° C.over 15 min. The resulting solution was stirred for 2 h at 40-45° C. inan oil bath. The resulting mixture was concentrated under vacuum. Theresidue was applied onto a silica gel column with CH₂Cl₂/methanol (5:1)providing 3.25 g (84%) of(3R)-1-[(1S,2S)-1-(4-bromo-2-methylphenoxy)-6-chloro-4-methyl-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperidin-3-amine(INT-TE7) as a red oil.

Step B: To a 250-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added arylbromide INT-TE7 (4.58 g, 9.58mmol, 1 equiv), dioxane (66 mL), benzylmercaptan (2.38 g, 192 mmol, 2equiv), Xantphos (665 mg, 1.15 mmol, 0.12 equiv), anddiisopropylethylamine (2.48 g, 19.2 mmol, 2 equiv), and Pd₂(dba)₃.CHCl₃(595 mg). The resulting solution was stirred overnight at 100° C. in anoil bath. The resulting mixture was concentrated under vacuum. Theresulting solution was diluted with water and extracted with 3×100 mL ofethyl acetate. The combined organic layers were washed with 2×200 mL ofbrine, dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum. The residue was applied onto a silica gel column withhexane/ethyl acetate (10%) providing 2.07 g (42%) of(3R)-1-[(1S,2S)-1-[4-(benzylsulfanyl)-2-methylphenoxy]-6-chloro-4-methyl-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperidin-3-amine(INT-TE8) as a light red oil. MS (m/z): 521 [M+H]⁺. ¹H NMR (Methanol-d4,300 MHz) δ 7.33-7.08 (m, 9H), 6.95 (d, J=1.1 Hz, 1H), 5.79 (d, J=6.3 Hz,1H), 4.04 (s, 2H), 3.43 (td, J=8.1, 6.2 Hz, 1H), 3.24 (dd, J=15.8, 8.1Hz, 1H), 3.06 (dd, J=30.1, 11.1 Hz, 2H), 2.77 (dd, J=15.9, 8.1 Hz, 1H),2.30 (s, 5H), 2.20-1.88 (m, 12H), 1.88-1.77 (m, 1H), 1.62 (t, J=12.8 Hz,1H), 1.28 (ddd, J=14.5, 6.8, 4.2 Hz, 2H).

Representative Scheme for the Synthesis of Dimer Products from DiamineLinkers:

Example 105:4-([(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide;tetra(trifluoroacetate)

Step A: To a 20 mL glass vial was added thioether INT-TE5 (0.530 g, 0.88mmol, 1 equiv), acetic acid (6.75 mL), and water (2.25 mL). ThenN-chlorosuccinimide (0.350, 2.62 mmol, 3 equiv) was added at roomtemperature. The resulting solution was stirred for 2 h at roomtemperature. The slurry was diluted with 50 mL of ethyl acetate andorganic solution was washed with 2×15 mL saturated aqueous sodiumbicarbonate and 1×15 mL brine. The organic layer was dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was applied onto a silica gel column with hexanes/ethyl acetate(0-30%) providing 0.429 g (84%) of tert-butyl4-((1S,2S)-1-(4-(benzylthio)-2-fluorophenoxy)-4,6-dichloro-2,3-dihydro-1H-inden-2-yl)piperazine-1-carboxylate(INT-TE9) as a white solid.

Step B: To a 5 mL glass vial was added of3-(2-[2-[(3R)-3-aminopyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-aminopyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)ureahydrochloride (INT-RD4, 96 mg, 0.15 mmol, 1 equiv), CH₂Cl₂ (0.5 mL), andtriethylamine (0.15 mL, 1.10 mmol, 8 equiv). The mixture stirred for 15minutes at room temperature, then solution of sulfonyl chloride INT-TE9(0.198 g, 0.34 mmol, 2.3 equiv) in CH₂Cl₂ (1.0 mL) was added dropwise.The reaction mixture stirred for 3 h at room temperature. The resultingmixture was concentrated under vacuum providing 0.270 g of crudetert-butyl4-((1S,2S)-1-(4-(N—((R)-1-(20-((R)-3-((4-(((1S,2S)-2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluorophenyl)sulfonamido)pyrrolidin-1-yl)-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)sulfamoyl)-2-fluorophenoxy)-4,6-dichloro-2,3-dihydro-1H-inden-2-yl)piperazine-1-carboxylate(INT-TE10) as a tan foam which was used for the next step withoutpurification.

Step C: To the crude material from Step B (theoretical 0.15 mmol) wasadded 4M hydrochloric acid in dioxane (1 mL) and the mixture was stirredfor 2 h at room temperature. The resulting slurry was concentrated undervacuum. The crude product was purified by preparative HPLC to providethe desired product.

Steps A-C provided the crude product which was purified by preparativeHPLC with the following conditions: Column, Atlantis Preparative T3 OBDColumn, 19*150 mm, 10 um; mobile phase, water (0.1% TFA) and CH₃CN(10.0% CH₃CN up to 70.0% in 40 min); Detector, UV 214 nm. This resultedin 0.061 g (22%) of the title compound as a white solid. MS (m/z): 686.2[M/2+H⁺. ¹H NMR (Methanol-d4, 400 MHz) δ 7.81-7.61 (m, 6H), 7.46 (d,J=1.7 Hz, 2H), 7.17 (s, 2H), 6.08 (d, J=5.7 Hz, 2H), 3.79-3.68 (m, 10H),3.54 (t, J=5.4 Hz, 5H), 3.40 (m, 6H), 3.28-3.18 (m, 16H), 3.13 (s, 6H),2.99 (dd, J=16.6, 7.5 Hz, 2H), 2.90-2.75 (m, 10H), 1.50 (s, 4H).

Example 106:4-([(1S2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolin-3-yl]-3-fluorobenzenesulfonamide;tetra(trifluoroacetate)

Beginning with INT-TE5 and INT-SD4, Steps A-C provided 121.8 mg (48%) ofthe title compound as a white solid. MS (m/z): 686.2 [M/2+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.77-7.65 (m, 6H), 7.44 (d, J=1.7 Hz, 2H), 7.16(d, J=1.2 Hz, 2H), 6.06 (d, J=5.7 Hz, 2H), 3.81-3.61 (m, 10H), 3.52 (t,J=5.3 Hz, 5H), 3.43 (m, 6H), 3.25-3.18 (m, 16H), 3.11 (s, 6H), 2.98 (dd,J=16.6, 7.2 Hz, 2H), 2.91-2.76 (m, 10H), 1.48 (s, 4H).

Example 107:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;tetra(trifluoroacetate)

Beginning with INT-TE6 and INT-SD4, Steps A-C provided 84.9 mg (34%) ofthe title compound as a white solid. MS (m/z): 659.4 [M/2+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.91 (d, J=8.9 Hz, 4H), 7.79 (d, J=1.7 Hz, 2H),7.46 (d, J=1.3 Hz, 2H), 7.36 (d, J=8.9 Hz, 4H), 6.09 (d, J=6.0 Hz, 2H),3.80-3.70 (m, 10E1), 3.54 (t, J=5.4 Hz, 5H), 3.48-3.33 (m, 11H), 3.24(t, J=5.1 Hz, 10H), 3.19-3.08 (m, 8H), 2.94-2.79 (m, 10H), 1.50 (s, 4H).

Example 108:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;tetra(trifluoroacetate)

Beginning with INT-TE6 and INT-RD4, Steps A-C provided 71.0 mg (26%) ofthe title compound as a white solid. MS (m/z): 659.3 [M/2+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.91 (d, J=8.9 Hz, 4H), 7.79 (d, J=1.9 Hz, 2H),7.46 (s, 2H), 7.36 (d, J=8.9 Hz, 4H), 6.09 (d, J=6.0 Hz, 2H), 3.78-3.71(m, 10H), 3.54 (t, J=5.3 Hz, 5H), 3.49-3.34 (m, 11H), 3.24 (t, 5.2 Hz,10H), 3.19-3.08 (m, 8H), 2.94-2.78 (m, 10H), 1.50 (s, 4H).

Example 109:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxo-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide;tetra(trifluoroacetate)

Beginning with INT-TE3 and INT-RD4, Steps A-C provided 74.0 mg (36%) ofthe title compound as a white solid. MS (m/z): 677.3 [M/2+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) 7.78 (d, J=1.8 Hz, 2H), 7.77-7.62 (m, 6H), 7.50(d, J=1.7 Hz, 2H), 6.08 (d, J=5.8 Hz, 2H), 3.81 (dd, J=13.8, 7.8 Hz,2H), 3.74 (t, J=5.0 Hz, 6H), 3.53 (t, 1=5.3 Hz, 5H), 3.46-3.31 (m, 11H),3.21 (m, 13H), 3.14 (dd, J=16.6, 7.4 Hz, 9H), 2.93-2.77 (m, 10H), 1.46(s, 4H).

Example 110:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide;tetra(trifluoroacetate)

Beginning with INT-TE3 and INT-SD4, Steps A-C provided 44.9 mg (17%) ofthe title compound as a white solid. MS (m/z): 677.3 [M/2+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.78 (d, J=1.8 Hz, 2H), 7.77-7.62 (m, 6H), 7.49(d, J=1.7 Hz, 2H), 6.07 (d, 0.1-5.8 Hz, 2H), 3.81 (dd, J=13.8, 7.8 Hz,2H), 3.74 (t, J=5.0 Hz, 6H), 3.53 (t, J=5.4 Hz, 5H), 3.47-3.31 (m, 11H),3.22 (dd, J=11.9, 7.3 Hz, 13H), 3.14 (dd, J=16.6, 7.4 Hz, 9H), 2.94-2.77(m, 10H), 1.45 (s, 4H).

Example 111:4-([(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicos)pyrrolidin-3-yl)-3-fluorobenzenesulfonamide;tetra(trifluoroacetate)

Beginning with INT-TE4 and INT-SD4, Steps A-B provided Example 111 whichwas purified by preparative HPLC with the following conditions: Column,Atlantis Preparative T3 OBD Column, 19*150 mm, 10 um; mobile phase,water (0.1% TFA) and CH₃CN (10.0% CH₃CN up to 60.0% in 40 min);Detector, UV 214 nm. This resulted in 15.9 mg (5.4%) of the titlecompound as a white solid. MS (m/z): 645.3 [M/2+H]⁺. ¹H NMR(Methanol-d4, 400 MHz): δ 7.83-7.74 (m, 4H), 7.67 (t, J=8.5 Hz, 2H),7.56 (d, J=1.7 Hz, 2H), 7.13 (s, 2H), 6.53 (d, 6.3 Hz, 2H), 3.76 (t,J=5.0 Hz, 7H), 3.68 (dd, J=16.8, 8.6 Hz, 2H), 3.55 (t, J=5.3 Hz, 7H),3.45 (m, 6H), 3.29-3.22 (m, 2H), 3.13 (s, 4H), 3.03 (s, 23H), 1.50 (s,4H).

Example 112:4-([(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)-3-fluorobenzenesulfonamide;tetra(trifluoroacetate)

Beginning with INT-TE4 and INT-RD4, Steps A-B provided Example 112 whichwas purified by preparative HPLC with the following conditions: Column,Atlantis Preparative T3 OBD Column, 19*150 mm, 10 um; mobile phase,water (0.1% TFA) and CH₃CN (10.0% CH₃CN up to 60.0% in 40 min);Detector, UV 214 nm. This resulted in 10.9 mg (3.1%) of the titlecompound as a white solid. MS (m/z): 645.3 [M/2+H]⁺. ¹H NMR(Methanol-d4, 400 MHz): δ 7.83-7.75 (m, 4H), 7.67 (t, J=8.2 Hz, 2H),7.56 (d, J=1.6 Hz, 2H), 7.13 (s, 2H), 6.52 (d, =6.1 Hz, 2H), 3.76 (t,J=5.0 Hz, 7H), 3.68 (dd, J=16.8, 8.7 Hz, 2H), 3.55 (t, 5.4 Hz, 7H), 3.46(m, 6H), 3.30-3.20 (m, 2H), 3.14 (s, 4H), 3.03 (s, 23H), 1.48 (s, 4H).

Example 113:4-([(1S,2S)-6-Chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamide;tetra(trifluoroacetate)

Beginning with INT-TE8 and INT-RD4 Steps A-B provided Example 113 whichwas purified by preparative HPLC with the following conditions: Column,Atlantis Preparative T3 OBD Column, 19*150 mm, 10 um; mobile phase,water (0.1% TFA) and CH₃CN (10.0% CH₃CN up to 60.0% in 40 min);Detector, UV 214 nm. This resulted in 16.9 mg (4.8%) of the titlecompound as a white solid. MS (m/z): 704.4 [M/2+H]⁺. ¹H NMR(Methanol-d4, 400 MHz): δ 7.80 (d, J=8.8 Hz, 2H), 7.73 (s, 2H), 7.47 (t,J 8.8 Hz, 2H), 7.18 (s, 2H), 6.96 (s, 2H), 6.05 (s, 2H), 3.82-3.69 (m,13H), 3.54 (m, 6H), 3.48-3.34 (m, 6H), 3.21 (dd, J=16.2, 8.0 Hz, 2H),3.13 (s, 4H), 2.92 (m, 2H), 2.87 (m, 23H), 2.28 (m, 25H), 1.50 (s, 4H).

Example 114:4-([(1S,2S)-6-Chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamide;tetra(trifluoroacetate)

Steps A-C were followed to prepare Example 114 with the addition of afree-basing of the initial amine INT-SD4 with basic resin (DowexMonosphere 550A hydroxide form) prior to addition of the sulfonylchloride in Step B. The crude product obtained was purified bypreparative HPLC with the following conditions: Column, AtlantisPreparative T3 OBD Column, 19*150 mm, 10 um; mobile phase, water (0.1%TFA) and CH₃CN (10% CH₃CN up to 60.0% in 40 min); Detector, UV 214 nm.This resulted in 68.0 mg (16%) of the title compound as a white solid.MS (m/z): 704.4 [M/2+H]⁺. ¹H NMR (Methanol-d4, 400 MHz): δ 7.84-7.67 (m,4H), 7.48 (t, J=8.8 Hz, 2H), 7.18 (s, 2H), 6.95 (s, 2H), 6.07 (d, J=5.8Hz, 2H), 3.82-3.69 (m, 13H), 3.54 (t, J=5.3 Hz, 6H), 3.48-3.34 (m, 6H),3.22 (dd, J=16.2, 8.0 Hz, 2H), 3.19 (s, 4H), 2.90 (m, 2H), 2.83 (m,23H), 2.29 (m, 25H), 1.47 (s, 4H).

Scheme for Dimer Product Synthesis via Stepwise Linker Construction:Example 115:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide;bis(trifluoroacetate)

Step A: tert-Butyl4-((1S,2S)-1-(4-(benzylthio)phenoxy)-6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)piperazine-1-carboxylate(580 mg, 1.00 mmol) was dissolved in CH₂Cl₂ (3 mL) and trifluoroaceticacid (0.5 mL, 6.52 mmol, 6.5 equiv) was added at 0° C. The reactionmixture was allowed to warm to room temperature and stirred for 18 h.The reaction mixture was diluted with ethyl acetate (50 mL) and washedwith 1M aqueous sodium hydroxide (2×10 mL), water (10 mL), and brine (10mL). The aqueous layers were back-extracted with ethyl acetate (20 mL).The combined organic layers were dried over sodium sulfate, filtered,and concentrated providing 500 mg of crude(1S,2S)-1-(4-(benzylthio)phenoxy)-6-chloro-2-(piperazin-1-yl)-2,3-dihydro-1H-indene-4-carbonitrile(INT-SLC1) as a brownish resin. MS (m/z): 476.2 [M+H]⁺.

Step B: To a solution of crude material INT-SLC1 from Step A(theoretical 1 mmol) in methanol (3 mL) was added ethyl trifluoroacetate(0.5 mL, 4.2 mmol) at room temperature. After stirring at roomtemperature for 1.5 h another portion of ethyl trifluoroacetate (0.3 mL,2.5 mmol) was added, followed by triethylamine (50 μL, 0.36 mmol). Thereaction mixture stirred for 1 h and then concentrated under vacuum. Theresidue was applied onto a silica gel column with hexanes/ethyl acetate(0-35%) providing 556 mg (97%) of(1S,2S)-1-[4-(benzylthio)phenoxy]-6-chloro-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-indene-4-carbonitrile(INT-SLC2) as a clear brownish oil. MS (m/z): 572.1 [M+H]⁺.

Step C: To a solution of thioether INT-SLC2 (556 mg, 0.97 mmol) in amixture of acetic acid (6.75 mL) and water (2.25 mL),N-chlorosuccinimide (388 mg, 2.91 mmol, 3 equiv) was added at roomtemperature. The reaction mixture stirred for 2 h at room temperatureand diluted with ethyl acetate (50 mL). The resulting solution waswashed with saturated aqueous sodium bicarbonate (2×15 mL) and brine (15mL). The organic layer was dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum providing 760 mg of crude4-([(1S,2S)-6-chloro-4-cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)benzene-1-sulfonylchloride (INT-SLC3) as a yellowish oil. MS (m/z): 548.0 [M+]⁺.

Step D: To a solution of crude material INT-SLC3 from Step C(theoretical 0.48 mmol) in CH₂Cl₂ (2 mL) was added tert-butyl4-aminopiperidine-1-carboxylate (147 mg, 0.74 mmol), followed bytriethylamine (95 μL, 0.67 mmol). The reaction mixture stirred for 20 hat room temperature and concentrated under vacuum. The residue wasapplied onto a silica gel column with hexanes/ethyl acetate (0-50%)providing 221 mg (65%) of tert-butyl4-([4-([(1S,2S)-6-chloro-4-cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidine-1-carboxylate(INT-SLC4) as a white solid. MS (m/z): 734.2 [M+Na]⁺.

Step E: To a solution of sulfonamide INT-SLC4 (50 mg, 0.07 mmol) inCH₂Cl₂ (0.7 mL) was added trifluoroacetic acid (0.05 mL, 0.87 mmol, 12.3equiv) and the mixture stirred for 20 h at room temperature. Thereaction mixture was diluted with CH₂Cl₂ (5 mL) and washed with 1Maqueous sodium hydroxide (2×2 mL) and brine (3 mL). The organic layerwas dried over anhydrous sodium sulfate, filtered, and concentratedproviding 50 mg of crude4-([(1S,2S)-6-chloro-4-cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-(piperidin-4-yl)benzenesulfonamide(INT-SLC5) as a white solid. MS (m/z): 612.2 [M+H]⁺.

Step F: The crude material INT-SLC5 from Step E (theoretical 0.07 mmol),4-[(tert-butoxycarbonyl)amino]butanoic acid (24.7 mg, 0.122 mmol, 1.7equiv), HATU (61.9 mg, 0.163 mmol, 2.3 equiv), and crushed 3 Å molecularsieves were suspended in DMF (0.8 mL). To this slurry was addeddiisopropylethylamine (56.7 μL, 0.326 mmol, 4.6 equiv) and the reactionmixture stirred for 2 h. The volatiles were removed under vacuum and theresidue was applied onto a silica gel column with CH₂Cl₂/methanol(0-10%) providing 50 mg (77%) of tert-butyl[4-(4-[4-([(1S,2S)-6-chloro-4-cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenylsulfonamido]piperidin-1-yl)-4-oxobutyl]carbamate(INT-SLC6) as a brownish solid. MS (m/z): 797.3 [M+H]⁺.

Step G: Trifluoroacetic acid (50 μL, 0.65 mmol, 10 equiv) was added to asolution of Boc-amine INT-SLC6 (50 mg, 0.063 mmol) in CH₂Cl₂ (0.7 mL).The reaction mixture stirred for 5 h at room temperature. Aftercompletion (TLC and LCMS), the reaction mixture was diluted in CH₂Cl₂ (4mL) and washed with 1M aqueous sodium hydroxide (2×1.5 mL) and brine(1.5 mL). The organic layer was dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum providing 45 mg of crudeN-[1-(4-aminobutanoyl)piperidin-4-yl]-4-([(1S,2S)-6-chloro-4-cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide(INT-SLC7) as a tan solid. MS (m/z): 697.2 [M+H]⁺.

Step H: To the solution of crude material INT-SLC7 from Step G(theoretical 0.063 mmol) in DMF (0.6 mL) was added1,4-diisocyanatobutane (3.5 mg, 0.025 mmol, 0.4 equiv). The reactionmixture was stirred for 15 h at room temperature. The reaction mixturewas concentrated under vacuum and the residue was applied onto a silica12 gel column with CH₂Cl₂/methanol (0-12%) providing 7 mg (18%) of4-[(1S,2S)-6-chloro-4-cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide(INT-SLC8) as a white solid. MS (m/z): 767.3 [M/2+H]⁺.

Step I: To a solution of dimer INT-SLC8 from Step H (7 mg, 0.0046 mmol)in methanol (0.3 mL) was added aqueous sodium hydroxide (3M, 10 μL, 0.03mmol, 6.5 equiv) at room temperature. The reaction mixture stirred for16 h at room temperature, concentrated under vacuum, and the residuepurified by reverse phase chromatography.

Compound 115:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide;bis(trifluoroacetate)

The crude product obtained through Steps A-I was purified by preparativeHPLC with the following conditions: Column, Atlantis Preparative T3 OBD,19*150 mm, 10 um; mobile phase, water (0.1% TFA) and CH₃CN (10.0% CH₃CNup to 70.0% in 40 min); Detector, UV 214 nm. This procedure provided 2.9mg (40%) of the title compound as a white solid. MS (m/z): 671.3[M/2+H]+. ¹H NMR (Methanol-d4, 400 MHz) δ 7.88 (d, J=8.8 Hz, 4H), 7.76(m, 2H), 7.45 (m, 2H), 7.31 (d, J=8.9 Hz, 4H), 6.05 (d, J=5.8 Hz, 2H),3.48-3.44 (m, 2H), 3.40-3.33 (m, 8H), 3.25-3.20 (m, 8H), 3.15-3.08 (m,14H), 2.92-2.76 (m, 16H), 2.39-2.32 (m, 4H), 1.74-1.66 (m, 4H), 1.47 (s,4H).

General Scheme for the Synthesis of Dimers with Peptidic Linkers:

Indane dimer products such as (II) are synthesized with aminoacid/peptidic linkers using the following methods.

Step A: The sulfonyl chloride INT-PL1, synthesized as outlined in thiswork, is combined with tert-butyl 3-aminopyrrolidine-1-carboxylate inCH₂Cl₂ with trimethylamine to provide the desired sulfonamide adductINT-PR2. The crude material is washed with water and brine, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theproduct is purified by normal phase chromatography to provide cleanINT-PL2.

Step B: The Boc-protected amine INT-PL2 is slurried in CH₂Cl₂ andtreated with trifluoroacetic acid. Once removal of the protecting groupis complete based on TLC and/or LCMS, the volatiles are removed undervacuum and the residue dissolved in ethyl acetate. The organic layer iswashed with saturated sodium bicarbonate and brine, dried over driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The product is purified by normal phase chromatography to provide cleanINT-PL3.

Step C: The amine product INT-PL3 is diluted in a suitable solvent suchas tetrahydrofuran or DMF and treated with a Boc-protected amino acid,diisopropylethylamine, and a coupling reagent such as HATU. Oncereaction is complete based on TLC and/or LCMS, the volatiles are removedunder vacuum and the residue dissolved in CH₂Cl₂ or other suitablesolvent. The organic layer is washed with saturated sodium bicarbonateand brine, dried over dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The product is purified by normal phasechromatography to provide clean INT-PL4.

Step D: The Boc-protected amine INT-PL4 is slurried in CH₂Cl₂ andtreated with trifluoroacetic acid. Once removal of the protecting groupis complete based on TLC and/or LCMS, the volatiles are removed undervacuum and the residue dissolved in ethyl acetate. The organic layer iswashed with saturated sodium bicarbonate and brine, dried over driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The product is purified by normal phase chromatography to provide cleanINT-PL5.

Steps C and D can be repeated to extend the linker peptide with moreamino acids as desired.

Step E: The amine INT-PL5 is diluted in DMF and treated with a limitingamount of 1,4-diisocyanatobutane. The resulting solution was stirred atroom temperature (or heated as required to drive completion). Theresulting mixture was concentrated under vacuum to provide crudeINT-PR6. If the product contains protecting groups such as tert-butylcarbamates or trifluoroacetamides, they are deprotected with theappropriate conditions at this stage. The final product of structure(II) is purified by preparative HPLC in watertCH₃CN and lyophilized toprovide the pure products as salts.

Through Steps A-E for the synthesis of compound of structure (II), thefollowing Examples are prepared.

Example 116:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl)pyrrolidin-3-yl]benzenesulfonamide

The title compound was prepared from INT-TE6 and Boc-Gly-OH. MS (m/z):629.3 [M/2+H]+. 1H NMR (Methanol-d4, 400 MHz) δ 7.80 (dd, J=13.3, 5.1Hz, 4H), 7.68 (t, J=2.0 Hz, 2H), 7.40 (d, J=6.4 Hz, 2H), 7.25 (dd,J=9.0, 7.0 Hz, 5H), 5.99 (d, J=6.7 Hz, 2H), 3.85-3.60 (m, 9H), 3.27 (d,J=16.6 Hz, 8H), 3.18-2.94 (m, 21H), 2.86-2.68 (m, 10H), 1.96-1.81 (m,1H), 1.40 (s, 4H).

Example 117:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-[(2S,13S)-14-[(S)-3-([4-[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2,13-dimethyl-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl]pyrrolidin-3-yl]benzenesulfonamide

The title compound is prepared from INT-TE6 and Boc-Ala-OH.

Example 118:N¹,N¹⁴-bis(2-[(S)-3-([4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide

The title compound was prepared from INT-TE6 and Boc-Gly-Gly-OH. MS(m/z): 686.3 [M/2+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ 7.88 (t, J=8.5Hz, 4H), 7.75 (s, 2H), 7.50 -7.45 (m, 2H), 7.32 (t, J=8.4 Hz, 4H), 6.07(s, 2H), 3.96-3.81 (m, 5H), 3.78 (d, J=4.1 Hz, 7H), 3.59-3.41 (m, 3H),3.18 (dt, J=32.4, 6.6 Hz, 20H), 2.87 (s, 9H), 1.50 (s, 4H).

Example 119:N¹,N¹⁴-bis(2-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yloxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide

The title compound was prepared from INT-TE6 and Boc-Gly-Gly-OH. MS(m/z): 686.3 [M/2+H]+. 1H NMR (Methanol-d4, 400 MHz) δ 7.87 (d, J=8.9Hz, 4H), 7.77-7.73 (m, 2H), 7.49-7.45 (m, 2H), 7.31 (d, J=8.9 Hz, 4H),6.09-6.03 (m, 2H), 3.78 (d, J=4.3 Hz, 11H), 3.58-3.32 (m, 2H), 3.26-3.04(m, 21H), 2.87 (s, 10H), 1.51 (s, 4H).

Example 120:N¹,N¹⁸-Bis(1-([4-([1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)piperidin-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide

The title compound is prepared from4-[(tert-butoxycarbonyl)amino]butanoic acid, tert-butylpiperidin-4-ylcarbamate, and INT-TE6.

Scheme for the Synthesis of Diastereomeric DimethylaminopiperidineAnalogs:

Example 121:4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide

Step A: To a 25-mL round-bottom flask was added aminoindanol INT-I8K(600 mg, 1.61 mmol, 1 equiv), tert-butylN-[2-([2-[2-[(4-hydroxybenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamate(736 mg, 1.82 mmol, 1.1 equiv), PPh₃ (629 mg, 2.40 mmol, 1.5 equiv), andTHF (3.7 mL). To the above was added DIAD (485 mg, 2.40 mmol, 1.50equiv) slowly at 45° C. over 25 min. The resulting solution was stirredfor 3 h at 45° C. and then concentrated under vacuum after diluting withCH₂Cl₂. The residue was applied onto a silica gel column withCH₂Cl₂/methanol (10:1) providing 920 mg (75%) of tell-butylN-[2-(2-[2-[(4-[[(1S,2S)-4-bromo-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamate(INT-DMP1) as a yellow oil.

Step B: To a To a 50-mL round-bottom flask purged and maintained with aninert atmosphere of nitrogen was added arylbromide INT-DMP1 (960 mg,1.26 mmol, 1 equiv), Zn(CN)₂ (82 mg, 0.55 equiv), NMP (10 mL), andPd(PPh3)₄ (147 mg, 0.13 mmol, 0.1 equiv). The resulting solution wasstirred overnight at 100° C. The resulting solution was diluted withwater and extracted with 3×50 mL of ethyl acetate. The combined organiclayers were dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with CH₂Cl₂/methanol (10:1) providing 600 mg (67%) of tert-butylN-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamate(INT-DMP2) as a yellow oil.

Step C: To a To a 100-mL round-bottom flask was added Boc-amine INT-DMP2(600 mg, 0.85 mmol, 1 equiv), CH₂Cl₂ (5 mL), and trifluoroacetic acid (ImL). The resulting slurry was stirred for 30 min at room temperature.The pH value of the solution was adjusted to 9 with saturated aqueoussodium bicarbonate and extracted with 5×20 mL of CH₂Cl₂. The combinedorganic layers were dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with CH₂Cl₂/methanol (10:1) providing 470 mg (91%) ofN-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene-1-sulfonamide(INT-DMP3) as a yellow oil.

Step D: To a To a 25-mL round-bottom flask was added amine INT-DMP3 (470mg, 0.78 mmol, 1 equiv), DMF (2 mL), and 1,4-diisocyanatobutane (48 mg,0.34 mmol, 0.45 equiv). The resulting solution was stirred for 1 h at60° C. The crude product was purified by preparative H PLC.

Example 121:4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide

The crude product was purified by Preparative HPLC with the followingconditions: Column, XBridge Preparative C18 OBD Column, 19*150 mm 5 um;mobile phase, Water (0.05% NH₄OH) and ACN (hold 47.0% ACN in 10 min);Detector, UV 254/220 nm. This resulted in 275.9 mg (26%) of3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]ureaas a white solid.

MS (m/z): 1353.7 [M+H]⁺. ¹H NMR (Methanol-d4, 300 MHz) δ 7.89-7.78 (m,4H), 7.72 (d, J=2.0 Hz, 2H), 7.50-7.42 (m, 2H), 7.37-7.26 (m, 4H), 5.99(d, J=5.9 Hz, 2H), 3.67-3.42 (m, 18H), 3.40-3.21 (m, 5H), 3.14-2.97 (m,12H), 2.86 (d, J=11.1 Hz, 2H), 2.35-2.22 (m, 2H), 2.15 (s, 16H), 1.93(d, J=11.8 Hz, 2H), 1.77 (d, J=13.4 Hz, 2H), 1.60-1.39 (m, 6H),1.29-1.13 (m, 3H).

Example 122:4-([(1S,2S)-6-Chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide

The title compound was prepared in the same manner as Example 121,beginning with the enantiomer (S)—N,N-dimethylpiperidin-3-amine. Thecrude product was purified by preparative HPLC with the followingconditions: Column, XBridge Shield RP18 OBD Column, 5 um, 19*150 mm;mobile phase, water (0.05% NH₄OH) and ACN (42.0% ACN up to 56.0% in 10min); Detector, UV 254 nm. This resulted in 93.7 mg (56%) of the titlecompound as a white solid. MS (m/z): 1353 [M+H]⁺. ¹H NMR (Methanol-d4,400 MHz) δ 7.91-7.83 (m, 4H), 7.76 (d, J=1.9 Hz, 2H), 7.52-7.47 (m, 2H),7.38-7.29 (m, 4H), 6.05 (d, J=5.9 Hz, 2H), 3.75 (td, J=7.9, 5.9 Hz, 2H),3.61-3.46 (m, 18H), 3.28 (d, J=5.4 Hz, 3H), 3.20-3.01 (m, 13H), 2.91 (s,2H), 2.76 (d, J=11.3 Hz, 2H), 2.62 (s, 12H), 2.50 (d, J=11.0 Hz, 2H),2.42 (d, J=10.8 Hz, 2H), 1.94 (s, 2H), 1.79 (d, J=12.8 Hz, 2H), 1.56 (s,4H), 1.51-1.43 (m, 4H).

Scheme for the Synthesis of Example 123: Example 123:4-([1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide]piperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl]piperidin-4-yl)benzenesulfonamide

Step A:4-[(1S,2S)-6-Chloro-4-cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-(piperidin-4-yl)benzenesulfonamide(INT-SLC5, 164 mg, 0.27 mmol), 2-(2-azidoethoxy)ethyl4-methylbenzenesulfonate (91.3 mg, 0.32 mmol, 1.2 equiv), and potassiumcarbonate (110 mg, 0.80 mmol, 3 equiv) were suspended in acetonitrile(2.5 mL) and the mixture stirred for 46 h at 50° C. The reaction mixturewas concentrated under vacuum and the residue was applied on silica gelcolumn dichloromethane/methanol (0-10%) providing 112 mg (58%) ofN-(1-[2-(2-azidoethoxy)ethyl]piperidin-4-yl)-4-([(1S,2S)-6-chloro-4-cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamidewas collected as a white solid. MS (m/z): 725.2 [M+H]⁺.

Step B: Platinum on carbon 5 wt. % (25 mg) was added to a solution ofINT-SLC9 (63 mg, 0.087 mmol) in ethyl acetate (2 mL). Threevacuum/hydrogen cycles were performed and the reaction mixture stirredunder hydrogen (1 atm) for 2 h at room temperature. The reaction mixturewas diluted with ethyl acetate and filtered through 0.2 μm Aerodisc®filter. The filtrates were concentrated under vacuum providing 55 mg ofcrudeN-(1-[2-(2-aminoethoxy)ethyl]piperidin-4-yl)-4-yl)-4-[(1S,2S)-6-chloro-4-cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamideproduct (INT-SLC10) as a white solid. MS (m/z): 699.3 [M+H]⁺.

Step C: Solution of 1,4-diisocyanatobutane (4.3 mg, 0.031 mmol, 0.39equiv) in dichloromethane (0.1 mL) was added to a solution of amineINT-SLC10 (55 mg, 0.079 mmol) in dichloromethane (1.2 mL) followed bytriethylamine (10 μL, 0.078 mmol). The reaction mixture stirred for 3 hat room temperature and concentrated under vacuum. The residue wasapplied onto a silica gel column gradient wash withdichloromethane/methanol (0-20%) followed bydichloromethane/methanol/triethylamine (80:20:2.5) providing 38 mg (80%)of4-([(1S,2S)-6-chloro-4-cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)piperidin-4-yl]benzenesulfonamideas a white solid. MS (m/z): 770.0 [M/2+H]⁺.

Step D: Aqueous sodium hydroxide (3M, 24 μL, 0.07 mmol, 3 equiv) wasadded to a solution of dimer from Step C (37 mg, 0.024 mmol) intetrahydrofuran/methanol (0.5:0.05 mL). The reaction mixture stirred for1.5 h at room temperature and then quenched with trifluoroacetic acid(50 μL) at 0° C. The mixture was concentrated under vacuum and theresidue purified by reverse phase chromatography to yield4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido]piperidin-1-yl)-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl]piperidin-4-yl)benzenesulfonamide(Example 123).

Representative Scheme for the Synthesis of N-Acylsulfonamide DimerProducts: Example 124:N¹,N¹⁸-Bis([4-[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide

Step A: The thioether intermediate INT-TE6 is deprotected by treatmentwith a protic acid such as trifluoroacetic acid or HCl.

Step B: The secondary amine of INT-NAI is protected as atrifluoroacetamide by treatment with ethyl trifluoroacetate in thepresence of a base such as triethylamine or pyridine.

Step C: The sulfonyl chloride INT-NA3 is obtained by oxidativechlorination with NCS or chlorine gas.

Step D: Treatment of the sulfonyl chloride with an ammonia equivalentthrough addition of ammonia in methanol or ammonium hydroxide yieldssulfonamide INT-NA4.

Step E: The N-acylsulfonamide is obtained through standard couplingconditions with the carboxylic acid using reagents including EDC, DCC,CDI, HATU, and the like, or alternatively, through reactions with acidchlorides, all in the presence of a suitable base such as triethylamineor pyridine.

Step F: The Boc-intermediate INT-NA5 is deprotected by treatment with aprotic acid such as trifluoroacetic acid or HCl.

Step G: Reaction of the amine INT-NA5 with a dual functional reagentsuch as 1,4-diisocyanatobutane yields the dimer product from whichprotecting groups are removed through treatment with appropriatereagents (such as 3M sodium hydroxide in methanol) to provide the finaldimer product.

Example 125:N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-1-[16-(4-[([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)carbamoyl]piperidin-1-yl)-5,12-dioxo-4,6,11,13-tetraazahexadecyl]piperidine-4-carboxamide

Representative Scheme for Synthesis of Piperazine Dimer Products:Example 126:4-([(1S,2S)-6-Chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide

Step A: As described previously in this work, epoxide INT-17B is reactedwith Boc-homopiperazine in CH₃CN at elevated temperature. The resultingmixture is concentrated under vacuum and purified on a silica gel columnto provide the aminoindanol INT-I8AA.

Step B: Aminoindanol INT-I8AA (1 equiv) and the thiophenol are mixed intetrahydrofuran (0.2M), heating to 40° C. To this slurry is added PPh₃(2 equiv) and DIAD (1.5 equiv). Upon completion of the reaction (LCMS orTLC), the resulting mixture is concentrated under vacuum and purified ona silica gel column to provide ether INT-18AB.

Step C: Aminoindanol INT-18AB (1 equiv), Zn(CN)₂ (0.60 equiv), Pd(PPh₃)₄(0.10 equiv), and NMP (0.4M) are combined at 95° C. Upon completion, thereaction slurry is cooled and extracted with 3× ethyl acetate. Thecombined organic layers are washed with 3× brine, dried over anhydroussodium sulfate, filtered, and concentrated. The residue is purified on asilica gel column providing the 4-cyano substituted aminoindanolINT-I8AC.

Step D: Thioether INT-I8AC (1 equiv) and acetic acid and water (9:1) arecombined in a flask followed by the addition of N-chlorosuccinimide(NCS, 5 equiv) in several batches. Upon completion, the resulting slurryis concentrated under vacuum and diluted with H₂O. The resultingsolution is extracted with of ethyl acetate and the organic layerscombined and washed with 3×H₂O and 1× brine. The mixture is dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue is purified on a silica gel column to provide the sulfonylchloride INT-I8AD.

Step E: Amine dimer INT-SD4 is slurried in CH₃CN and water (added asnecessary for solubility) followed by the addition of sulfonyl chlorideINT-I8AD and diisopropylethylamine. The reaction mixture is agitateduntil completion (as determined by TLC or LCMS) and concentrated undervacuum. The residue is diluted in CH₂Cl₂ and washed with 2×1M NaHSO₄ andbrine, dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum. The residue is purified on a silica gel column providingthe Boc-protected dimer product. Subsequently, the material is treatedwith trifluoracetic acid in CH₂Cl₂ to remove the protecting groups andthe resulting mixture purified by reverse phase preparative HPLC.

The crude product was purified by preparative HPLC with the followingconditions: Column, XBridge Shield RP18 OBD Column, 5 um, 19*150 mm;mobile phase, water (0.05% TFA) and ACN (13.0% ACN up to 36.0% in 8min); Detector, UV 254 nm. This resulted in 188 mg (69%) of the titlecompound as a white solid. MS (m/z): 1345.65 [M+H]⁺. ¹H NMR(Methanol-d4, 400 MHz) δ 7.94 (d, J=8.6 Hz, 2H), 7.80 (d, J=1.9 Hz, 1H),7.51 (d, J=1.7 Hz, 1H), 7.39 (d, J=8.8 Hz, 2H), 6.09 (d, J=5.9 Hz, 1H),4.00 (q, J=7.4 Hz, 2H), 3.78 (t, 4.9 Hz, 2H), 3.56 (t, J=5.3 Hz, 2H),3.50-3.36 (m, 2H), 3.33-3.23 (m, 2H), 3.20-3.05 (m, 5H), 2.95 (t, J=6.0Hz, 2H), 2.37 (s, 1H), 2.04 (dd, J=10.1, 4.0 Hz, 3H), 1.52 (s, 2H).

Example 127:4-([(1S,2S)-6-Chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;bis(trifluoroacetic acid)

The crude product was purified by preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19 mm*250 mm, 5μm; mobile phase, water (0.05% TFA) and ACN (24.0% ACN up to 42.0% in 9min); Detector, UV 254 nm. This resulted in 128.3 mg (70%) of the titlecompound as a white solid. MS (m/z): 1348 [M+H]⁺. ¹H NMR (Methanol-d4,300 MHz) δ 7.89 (d, J=8.8 Hz, 2H), 7.75 (d, J=1.9 Hz, 1H), 7.46 (s, 1H),7.34 (d, J=8.8 Hz, 2H), 6.03 (d, J=5.8 Hz, 1H), 4.87-4.77 (m, 1H),4.00-3.89 (m, 2H), 3.73 (t, J=4.9 Hz, 2H), 3.52 (t, J=5.2 Hz, 2H),3.43-3.31 (m, 3H), 3.28-3.01 (m, 6H), 2.89 (t, J=6.0 Hz, 2H), 2.04-1.94(m, 3H), 1.47 (s, 2H).

Example 128:4-([(1S,2S)-6-Chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide

Example 129:4-([(1S,2S)-6-Chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)benzenesulfonamide

Example 130:4-([(1S,2S)-2-[(1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-2-1(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;bis(trifluoroacetic acid)

The crude product was purified by Preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 10 μm, 19*250mm; mobile phase, water (0.05% TFA) and ACN (23.0% ACN up to 41.0% in 8min); Detector, UV 254 nm. This resulted in 209 mg (51%) of the titlecompound as a white solid. MS (m/z): 1343 [M+H]⁺. ¹H NMR (Methanol-d⁴′400 MHz) δ 7.96-7.88 (m, 4H), 7.76 (d, J=1.9 Hz, 2H), 7.40-7.32 (m, 6H),6.05 (d, J=6.9 Hz, 2H), 4.27 (s, 2H), 3.99 (s, 4H), 3.91-3.80 (m, 4H),3.75 (t, J=5.0 Hz, 6H), 3.64-3.40 (m, 14H), 3.21 (dd, J=11.5, 2.4 Hz,6H), 3.15-3.01 (m, 10H), 2.95-2.87 (m, 2H), 2.47-2.07 (m, 4H), 2.01 (s,2H), 1.85 (d, J=11.6 Hz, 2H), 1.49 (s, 4H).

Example 131:4-([(1S,2S)-2-[(1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;bis(trifluoroacetic acid)

The crude product was purified by preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 10 μm, 19 mm×250mm; mobile phase, water (0.05% TFA) and ACN (23.0% ACN up to 41.0% in 8min); Detector, UV 254 nm. This resulted in 288.8 mg (63%) of the titlecompound as a white solid. MS (m/z): 1343 [M+H]⁺. ¹H NMR (Methanol-d4,400 MHz) δ 7.96-7.88 (m, 4H), 7.77 (d, J=1.8 Hz, 2H), 7.40-7.32 (m, 6H),6.06 (d, J=6.9 Hz, 2H), 4.30-4.25 (m, 2H), 3.99 (s, 2H), 3.93-3.81 (m,5H), 3.75 (1, J=5.0 Hz, 7H), 3.65-3.36 (m, 16H), 3.21 (dd, J=11.6, 2.4Hz, 4H), 3.15-3.01 (m, 10H), 2.97-2.89 (m, 2H), 2.49-2.06 (m, 4H), 2.00(s, 2H), 1.86 (d, J=11.3 Hz, 2H), 1.49 (s, 4H).

Example 132:4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfinamide;bis(trifluoroacetic acid)

The crude product was purified by Preparative HPLC with the followingconditions: Column, XBridge Shield RP18 OBD Column, 5 um, 19*150 mm;mobile phase, water (0.05% TFA) and ACN (12% ACN up to 38% in 8 min);Detector, UV 220 nm. This resulted in 180.1 mg (59%) of the titlecompound as a white solid. MS (m/z): 1347.7 [M+H]⁺. ¹H NMR (Methanol-d4,300 MHz) δ 7.93-7.83 (m, 4H), 7.75 (d, J=1.9 Hz, 2H), 7.43 (d, J=1.8 Hz,2H), 7.38-7.29 (m, 4H), 6.12-6.03 (m, 2H), 3.96 (s, 2H), 3.74 (q, J=6.6,5.1 Hz, 10H), 3.51 (t, J=5.2 Hz, 4H), 3.43-3.27 (m, 16H), 3.19-2.97 (m,15H), 2.63 (t, J=10.8 Hz, 2H), 2.41-2.27 (m, 3H), 2.00 (s, 1H), 1.47 (s,4H), 1.27 (d, J=6.6 Hz, 6H).

Example 133:4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;bis(trifluoroacetic acid)

The crude product was purified by preparative HPLC with the followingconditions: Column, XBridge Preparative OBD C18 Column, 19*250 mm, 5 μm;mobile phase, water (0.0.5% TFA) and ACN (25% ACN up to 40% in 9 min);Detector, UV 220 nm. This resulted in 218.9 mg (54%) of the titlecompound as a white solid. MS (m/z): 1348 [M+H]⁺. ¹H NMR (Methanol-d4,300 MHz) δ 7.88 (d, J=8.8 Hz, 4H), 7.75 (d, J=1.9 Hz, 2H), 7.47-7.40 (m,2H), 7.38-7.29 (m, 4H), 6.08 (d, J=6.0 Hz, 2H), 3.74 (q, J=6.8, 5.2 Hz,8H), 3.51 (t, J=5.2 Hz, 7H), 3.43-3.27 (m, 10H), 3.19-2.97 (m, 21H),2.63 (t, J=11.2 Hz, 2H), 2.34 (dd, J=12.6, 10.2 Hz, 2H), 2.00 (s, OH),1.47 (s, 4H), 1.27 (d, J=6.6 Hz, 6H).

Example 134:4-([(1S,2S)-6-Chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;bis(trifluoroacetic acid)

The crude product was purified by preparative HPLC with the followingconditions: Column, XBridge Shield RP18 OBD Column, 5 μm, 19*150 mm;mobile phase, water (0.05% TFA) and ACN (12.0% ACN up to 38.0% in 8min); Detector, UV 220 nm. This resulted in 257.5 mg (51%) of the titlecompound as a white solid. MS (m/z): 1346 [M+H]⁺. ¹H NMR (Methanol-d4,400 MHz) δ 7.97-7.89 (m, 4H), 7.80 (d, J=1.8 Hz, 2H), 7.53-7.48 (m, 2H),7.42-7.34 (m, 4H), 6.10 (d, J=5.9 Hz, 2H), 4.01 (s, 2H), 3.86-3.71 (m,10H), 3.56 (t, J=5.3 Hz, 5H), 3.50-3.40 (m, 15H), 3.24-3.05 (m, 14H),2.67-2.56 (m, 2H), 2.49 (dd, J=12.8, 10.2 Hz, 2H), 2.36 (s, 2H), 2.02(s, 2H), 1.52 (s, 4H), 1.29 (d, J=6.6 Hz, 6H).

Example 135:4-([1S,2S)-6-Chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;bis(trifluoroacetic acid

The crude product was purified by preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm, 5 μm;mobile phase, water (0.05% TFA) and ACN (25.0% ACN up to 43.0% in 9min); Detector, UV 254 nm. This resulted in 226.5 mg (44%) of the titlecompound as a white solid. MS (m/z): 1346 [M+H]⁺. ¹H NMR (Methanol-d4,400 MHz) δ 7.97-7.89 (m, 4H), 7.80 (d, J=1.9 Hz, 2H), 7.53-7.48 (m, 2H),7.42-7.34 (m, 4H), 6.10 (d, J=5.9 Hz, 2H), 4.01 (s, 2H), 3.86-3.74 (m,10H), 3.56 (t, J=5.3 Hz, 4H), 3.44-3.34 (m, 16H), 3.24-3.06 (m, 14H),2.68-2.56 (m, 2H), 2.54-2.43 (m, 2H), 2.36 (s, 2H), 2.01 (s, 2H), 1.51(d, J=5.9 Hz, 4H), 1.29 (d, J=6.6 Hz, 6H).

Example 136:4-([(1S,2S)-6-Chloro-4-cyano-2-1(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-1(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;bis(trifluoroacetic acid

The crude product was purified by preparative HPLC with the followingconditions: Column, XBridge C18 OBD Preparative Column, 10 μm, 19*250mm; mobile phase, water (0.05% TFA) and ACN (25% ACN up to 43% in 8min); Detector, UV 254 nm. This resulted in 254 mg (84%) of the titlecompound as a white solid. MS (m/z): 1376 [M+H]⁺. ¹H NMR (Methanol-d4,300 MHz) δ 7.88 (d, J=8.7 Hz, 4H), 7.76 (d, J=1.9 Hz, 2H), 7.45 (s, 2H),7.33 (d, J=8.9 Hz, 4H), 6.07 (d, J=6.0 Hz, 2H), 3.96 (s, 3H), 3.74 (dt,J=9.6, 5.6 Hz, 10H), 3.51 (t, J=5.2 Hz, 4H), 3.41-3.28 (m, 14H),3.20-3.07 (m, 12H), 2.30 (dt, J=28.3, 11.9 Hz, 5H), 1.99 (s, 3H), 1.47(s, 4H), 1.25 (dd, J=9.3, 6.6 Hz, 13H).

Example 137:4-([(1S,2S)-6-Chloro-4-cyano-2-1(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-1(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;bis(trifluoroacetic acid)

The crude product was purified by preparative HPLC with the followingconditions: Column, XBridge Shield RP18 OBD Column, 5 um, 19*150 mm,mobile phase, water (0.05% TFA) and ACN (13% ACN up to 40% in 8 min);Detector, UV 220 nm. This resulted in 171 mg (42%) of the title compoundas a white solid. MS (m/z): 1375.6 [M+H]⁺. ¹H NMR (Methanol-d4, 300 MHz)δ 7.88 (d, J=8.7 Hz, 4H), 7.76 (d, J=1.8 Hz, 2H), 7.46 (d, J=1.8 Hz,2H), 7.38-7.29 (m, 4H), 6.07 (d, J=5.9 Hz, 2H), 3.96 (s, 2H), 3.74 (dt,J=9.9, 5.6 Hz, 10H), 3.51 (t, J=5.2 Hz, 5H), 3.41-3.28 (m, 13H),3.20-3.06 (m, 13H), 2.30 (dt, J=27.3, 11.9 Hz, 6H), 1.97 (s, 2H), 1.48(d, J=5.3 Hz, 4H), 1.25 (dd, J=9.7, 6.6 Hz, 13H).

Example 138:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-2-oxopiperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)-2-oxopiperidin-3-yl]benzenesulfonamide

Example 139:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-2-oxoazepan-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)-2-oxoazepan-3-yl]benzenesulfonamide

Scheme for the Synthesis of Cyclohexyl Core Dimer Products: Example 140:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[2-(2-[2-(3-[(1s,4s)-4-(3-[2-(2-[2-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)ethoxy]ethoxy)ethyl]ureido)cyclohexyl]ureido)ethoxy]ethoxy)ethyl]benzenesulfinamide

Step 1: The amine INT-M5E is treated with disuccinimidyl carbonate (DSC)or similar activating agent (others including 1,1′-carbonyldiimidazole,p-nitrophenylchloroformate, etc) in DMF, followed by addition of thedesired diamine, with (1s,4s)-cyclohexane-1,4-diamine shown.Bis(2,5-dioxopyrrolidin-1-yl)carbonate (85 mg, 0.33 mmol, 1.1 eq) andtert-butyl 4-((1S,2S)-2-(4-(N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-4-chloro-6-cyano-2,3-dihydro-1H-inden-1-yl)piperazine-1-carboxylate(200 mg, 0.3 mmol) were stirred in DMF (1 mL) for 1.5 hours before asolution of (1s,4s)-cyclohexane-1,4-diamine (15.5 mg, 0.135 mmol, 0.45eq) in DMF (0.2 mL) was added. The mixture was stirred for 2 h at 60° C.LCMS showed significant amount of monourea side-product, example 155.The DMF was removed under vacuum, residue dissolved in 4:1 MeCN: H2O,filtered, and purified by prep-HPLC with the following conditions:Column, Atlantis Prep T3 OBD, 50*250 mm, 10 um; mobile phase, water(0.1% TFA) and CH3CN (25.0% CH3CN up to 80.0% in 60 min); Detector, UV214 nm. Product eluted ˜62% MeCN. Boc-protected cyclohexyl diamineproduct: 143 mg (61%); LCMS: ret time 3.3 min. MS (m/z): [M/2+H]+ 747.4.The product was deprotected in the following step.

Step 2: The product was deprotected under acidic conditions yieldingExample 140. LCMS: ret time 2.40 min, [M/2+H]⁺ 647.3. ¹H NMR(Methanol-d4, 400 MHz) δ 7.86 (d, J=9.0 Hz, 4H), 7.76 (d, J=1.9 Hz, 2H),7.45 (d, J=1.2 Hz, 2H), 7.31 (d, J=9.0 Hz, 4H), 6.06 (d, J=6.2 Hz, 2H),3.79-3.67 (m, 1H), 3.62-3.44 (m, 22H), 3.33 (s, 3H), 3.22 (t, J=5.1 Hz,8H), 3.05 (t, J=5.5 Hz, 4H), 2.85 (d, J=14.3 Hz, 5H), 1.70-1.46 (m, 4H)

Example 141:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[2-(2-[2-(3-[(1r,4r)-4-(3-[2-(2-[2-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)ethoxy]ethoxy)ethyl]ureido)cyclohexyl]ureido)ethoxy]ethoxy)ethyl]benzenesulfonamide

The title compound was prepared from (1r,4r)-cyclohexane-1,4-diamine andINT-M5E through the route to prepare Example 140. LCMS: ret time 2.37min. MS (m/z): [M/2+H]⁺ 647.3. ¹H NMR (Methanol-d4, 400 MHz) δ 7.91-7.82(m, 4H), 7.76 (d, J=1.9 Hz, 2H), 7.46 (d, J=1.2 Hz, 2H), 7.38-7.23 (m,4H), 6.07 (d, J=6.1 Hz, 2H), 3.80-3.66 (m, 2H), 3.61-3.44 (m, 18H), 3.36(dd, J=16.7, 8.0 Hz, 4H), 3.24 (dt, J=15.3, 5.4 Hz, 13H), 3.12 (dd,J=16.6, 8.1 Hz, 2H), 3.05 (t, J=5.5 Hz, 4H), 2.86 (qd, J=13.0, 7.9 Hz,8H), 1.88 (d, J=6.3 Hz, 4H), 1.21 (dd, J=10.9, 9.2 Hz, 4H).

Example 142:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(18-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide

The title compound is prepared through the sequence employed inpreparation of Example 116, but beginning with Boc-4-aminobutyric acidand 1-Boc-(R)-3-aminopyrrolidine.

Example 143:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(18-[(1S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide

The title compound is prepared through the sequence employed inpreparation of Example 116, but beginning with Boc-4-aminobutyric acidand 1-Boc-(S)-3-aminopyrrolidine.

Example 144:(S)—N-([4-([1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-1-(20-[(S)-3-[([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)carbamoyl]pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidine-3-carboxamide

The title compound was prepared through the procedure provided forExample 124 beginning with N-Boc-L-beta-proline. MS (m/z): 687.3[M/2+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ 8.12-7.98 (m, 4H), 7.81-7.77(m, 2H), 7.48-7.44 (m, 2H), 7.41-7.28 (m, 4H), 6.12-6.06 (m, 2H), 3.76(s, 9H), 3.59-3.50 (m, 6H), 3.25 (s, 14H), 3.19-3.07 (m, 9H), 2.96-2.74(m, 9H), 1.57-1.43 (m, 4H).

Example 145:(R)—N-([4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-1-(20-[(R)-3-[([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)carbamoyl]pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidine-3-carboxamide

The title compound is prepared through the procedure provided forExample 124 beginning with N-Boc-D-beta-proline.

Scheme for the Synthesis of Monomer Products:

“Monomer” final products are described previously in this work orobtained through deprotection (as necessary) of analogs such as theINT-M2 series of compounds. Additionally, “monomers” are obtainedthrough the steps listed in the above scheme, beginning with sulfonylchloride A, prepared through oxidative chlorination as previouslydescribed in this work. These materials A are reacted with anycommercial or synthetic amine (primary or secondary) compounds,including those with protecting groups PG, in the presence of bases liketriethylamine, pyridine, or metal carbonates. The product sulfonamides Bare deprotected as necessary to produce “monomer” products of structureC.

The following Example of products can also be prepared using thesynthetic routes described herein:

Example 146:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide

Example 147:N-(2-[2-(2-Aminoethoxy)ethoxy]ethyl)-4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide

Example 148:N-[1-(4-Aminobutanoyl)piperidin-4-yl]-4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide

Example 149:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-(3-oxo-7,10-dioxa-2,4-diazadodecan-12-yl)benzenesulfinamide

Example 150:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-(1-[4-(3-methylureido)butanoyl]piperidin-4-yl)benzenesulfonamide

Example 151:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-yl]benzenesulfonamide

Example 152:4-([4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-yl]piperidine-1-carboxamide

Other Synthetic Schemes

According to the General Scheme for the synthesis of compounds ofstructure (III), the elaborated structures such as INT-MON1, “monomers”,are dimerized to the symmetric urea (Ill) through reaction with1,1′-carbonyldiimidazole or p-nitrophenylchloroformate or the like.Through this step, compounds such as Example 153-155 are prepared.

Example 153:4-(3-[14-([4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-4-oxobutyl]ureido)-N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)butanamide

Example 154:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(4-[3-(4-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-4-oxobutyl)ureido]butanoyl)piperidin-4-yl]benzenesulfonamide

Example 155:4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[19-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecyl]benzenesulfonamide

Step A: Bis(2,5-dioxopyrrolidin-1-yl)carbonate (85 mg, 0.33 mmol, 1.1eq) and tert-butyl 4-((1S,2S)-2-(4-(N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-4-chloro-6-cyano-2,3-dihydro-1H-inden-1-yl)piperazine-1-carboxylate(200 mg, 0.3 mmol) were stirred in DMF (1 mL) for 1.5 hours before asolution of (1s,4s)-cyclohexane-1,4-diamine (15.5 mg, 0.135 mmol, 0.45eq) in DMF (0.2 mL) was added. The mixture was stirred for 2 h at 60° C.LCMS showed significant amount of monourea side-product, example 155.The DMF was removed under vacuum, residue dissolved in 4:1 MeCN: H2O,filtered, and purified by prep-HPLC with the following conditions:Column, Atlantis Prep T3 OBD, 50*250 mm, 10 um; mobile phase, water(0.1% TFA) and CH3CN (25.0% CH3CN up to 80.0% in 60 min); Detector, UV214 nm. Product eluted ˜62% MeCN. Cyclohexyl diamine product: 143 mg(61%); LCMS: ret time 3.3 min. MS (m/z): [M/2+H]+ 747.4. Symmetric ureaproduct: 47 mg (22%); LCMS: ret time 3.4 min MS (m/z): [M/2+H]+ 677.3.The products were each deprotected in the following step.Step B: Representative procedure (Example 155): TFA (150 μL, 1.95 mmol,69 eq) was added to a solution of tert-butyl4-((1S,2S)-1-(4-(N-(19-((4-(((1S,2S)-2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)sulfonamido)-10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecyl)sulfamoyl)phenoxy)-6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)piperazine-1-carboxylate(45 mg, 0.028 mmol) in DCM (1.0 mL). The mixture was stirred for 4 hours(complete by LCMS). The volatiles were removed under vacuum and theresidue dissolved in 4:1 MeCN:H2O and purified by prep-HPLC with thefollowing conditions: Column, Atlantis Prep T3 OBD, 50*250 mm, 10 um;mobile phase, water (0.1% TFA) and CH3CN (25.0% CH₃CN up to 60.0% in 50min); Detector, UV 214 nm. Product eluted at 50% MeCN, 25 mg (55%) wascollected Example 155 as a white solid. LCMS: ret time 2.40 min. MS:[M/2+H]⁺ 577.3. ¹H NMR (Methanol-d4, 400 MHz) δ 7.86 (d, J=9.0 Hz, 4H),7.76 (d, J=1.9 Hz, 2H), 7.47-7.44 (m, 2H), 7.31 (d, J=9.0 Hz, 4H),6.08-6.04 (m, 2H), 3.78-3.67 (m, 1H), 3.61-3.43 (m, 21H), 3.40-3.32 (m,2H), 3.27 (s, 4H), 3.22 (t, J=5.2 Hz, 10H), 3.16-3.08 (m, 1H), 3.05 (s,5H), 2.93-2.77 (m, 8H).

Example 156:4-([(1S,2S)-6-Chloro-4-amido-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-amido-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfinamide

The title compound is prepared through controlled hydrolysis of Example41, via the use of either protic acids including sulfuric acid orhydrogen chloride or aqueous bases such as sodium hydroxide.

Example 157:4-([(1S,2S)-4-Cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-4-cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide

The title compound is prepared through the same procedures as yieldExample 41, beginning with the 4-methyl-2-bromobenzaldehyde or similarappropriate starting material.

Scheme for the Synthesis of Bicyclic Analogs:

According to the General Scheme for the Synthesis of Bicyclic Analogs,compounds of structure (IV) are prepared from starting materials such asphenol A. With or without protection of the phenolic oxygen, compounds Bare prepared via alkylation or acylation with a suitable reagent such asalkyl halides, carboxylic acids, isocyanates, etc using bases orcoupling agents known to those in the art. Subsequently the linker ofcompound B, containing a reactive or masked substituent Y, is reactedwith a bisfunctional reagent such as 1,4-diisocyanatobutane or the liketo generate a dimer C. Compounds of structure (IV) are generated bycoupling of C with D under Mitsunobu conditions with diazocarboxylatereagents (DEAD, DIAD, etc) and triphenylphosphine or throughmesylation/displacement in the presence of base.

Example 158:1,1′-(Butane-1,4-diyl)bis[3-(4-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinolin-2(1H)-yl]-4-oxobutyl)urea]

Example 159:1,1′-(Butane-1,4-diyl)bis[3-(4-[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinolin-2(1H)-yl]-4-oxobutyl)urea]

Example 160:N,N′-(6,14-Dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide]

Example 161:N,N′-(6,14-Dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide]

Example 162:1,1′-(Butane-1,4-diyl)bis(3-[2-(2-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindolin-2-yl]ethoxy)ethyl]urea)

Example 163:1,1′-(Butane-1,4-diyl)bis(3-[2-(2-[5-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindolin-2-yl]ethoxy)ethyl]urea)

Example 164:4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(18-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-((R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide

Example 165:4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(18-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide

Example 166:4-[(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-((R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl)benzenesulfonamide

Example 167:N¹,N¹⁴-Bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide

Example 168:4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)piperidin-4-yl]benzenesulfonamide

Example 169: 4-([(1S,2S)-4,6-Dichloro-2-1.(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-KR)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide

Example 170:N¹,N¹⁴-Bis(2-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide

Example 171:4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(18-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-lii-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide

Step A:4-(((1S,2S)-6-Chloro-4-cyano-2-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-N—((S)-pyrrolidin-3-yl)benzenesulfonamide(prepared by procedures analogous to the INT-SECS, 200 mg, 0.33 mmol),4-((tert-butoxycarbonyl)amino)butanoic acid (100 mg, 0.49 mmol, 1.5equiv), HATU (247 mg, 0.65 mmol, 2 equiv), and crushed molecular sieves(3 Å) were suspended in dimethylformamide (1.0 mL), thendiisopropylethylamine (226 μL, 1.3 mmol, 4 equiv) was added at roomtemperature. The mixture was stirred for 30 min at room temperature atwhich point the reaction was complete by LC/MS. The reaction mixture wasconcentrated under vacuum and the residue was purified by silica gelchromatography with DCM:MeOH 0 to 8%. Product eluted ˜6% MeOH; 250 mg(97%) was collected as tan solid. LC/MS: retention time 4.06 minutes. MS(m/z): [M+H]⁺ 797.2.

Step B: TEA (190 μL, 2.5 mmol, 8.0 equiv) was added to a solution oftert-butyl(4-((S)-3-(4-(((1S,2S)-6-chloro-4-cyano-2-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)oxy)phenylsulfonamido)pyrrolidin-1-yl)-4-oxobutyl)carbamate(250 mg, 0.31 mmol) in DCM (1.0 mL). The reaction mixture was stirredfor 16 h at rt, then concentrated under vacuum (azeotroping TEA withDCE) providing crude product (theoretical 0.31 mmol) as a white foam,which was used for the next step without purification. LCMS: retentiontime 3.22 minutes. MS (m/z): [M+H]⁺ 697.2.Step C: 1,4-Diisocyanatobutane (18.6 mg, 0.13 mmol, 0.43 equiv) wasadded to a solution of2N—(S)-1-(4-aminobutanoyl)pyrrolidin-3-yl)-4-(((1S,2S)-6-chloro-4-cyano-2-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)oxy)benzenesulfonamide(216 mg, 0.31 mmol) in DMF (1.0 mL) and Et₃N (213 μL, 1.54 mmol, 5equiv). The reaction mixture was stirred for 4 h at room temperature,diluted with H₂O/MeCN, and purified by prep-HPLC with the followingconditions: Column, Atlantis Prep T3 OBD, 19*150 mm, 10 um; mobilephase, water (0.1% TFA) and CH₃CN (20.0% CH₃CN up to 80.0% in 40 min);Detector, UV 214 nm. Product eluted ˜77% MeCN. This procedure provided170.1 mg (83%) of the title compound as a white solid. LC/MS: retentiontime 4.31 minutes. MS (m/z): [M/2+H]⁺ 767.3.Step D: 3M aq NaOH (185 μL, 0.55 mmol, 5.0 eq) was added to a solutionof(S,S,R)—N,N′-((3S,3′S)-1,1′-(6,13-dioxo-5,7,12,14-tetraazaoctadecane-1,18-dioyl)bis(pyrrolidine-3,1-diyl))bis(4-(((1S,2S)-6-chloro-4-cyano-2-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)oxy)benzenesulfonamide)(170 mg, 0.11 mmol) in THF/methanol (0.9:0.1 mL). The reaction mixturewas stirred for 4 h at rt—complete by LC/MS. The reaction mixture wasdiluted in H₂O/MeCN and purified by prep-HPLC with the followingconditions: Column, Atlantis Prep T3 OBD, 19*150 mm, 10 μm; mobilephase, water (0.1% TFA) and CH₃CN (10.0% CH₃CN up to 60.0% in 40 min);Detector, UV 214 nm. Product eluted ˜48% MeCN. This procedure provided124 mg (72%) of the title compound as a white solid. LC/MS: retentiontime 2.9 minutes. MS (m/z): [M/2+H]⁺ 671.3. ¹H NMR (Methanol-d4, 400MHz) δ 7.92-7.83 (m, 4H), 7.76 (s, 2H), 7.49-7.45 (m, 2H), 7.37-7.25 (m,4H), 6.09-6.05 (m, 2H), 3.86-3.69 (m, 2H), 3.34 (dd, J=14.5, 6.4 Hz,19H), 3.11 (t, J=8.6 Hz, 22H), 2.69-2.55 (m, 1H), 2.41-2.04 (m, 1H),1.98-1.62 (m, 1H), 1.47 (s, 4H), 1.28 (dd, J=6.5, 3.7 Hz, 711).

Example 172:4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide

Step A:4-(((1S,2S)-6-Chloro-4-cyano-2-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-N-(piperidin-4-yl)benzenesulfonamide(prepared by procedures analogous to INT-SLC5, 170 mg, 0.27 mmol),4-((tert-butoxycarbonyl)amino)butanoic acid (83 mg, 0.40 mmol, 1.5equiv), HATU (206 mg, 0.54 mmol, 2 equiv) and crushed molecular sieves(3 Å) were suspended in dimethylformamide (1.0 mL), thendiisopropylethylamine (190 μL, 1.1 mmol, 4 equiv) was added at roomtemperature. The reaction mixture was stirred for 1 h at roomtemperature—complete by LC/MS. The reaction mixture was concentratedunder vacuum and the residue was purified by silica gel chromatographywith DCM:MeOH 0 to 8%. Product eluted ˜6% MeOH; 210 mg (96%) wascollected as a tan solid. LC/MS: retention time 4.11 minutes. MS (m/z):[M+H]⁺ 811.2.Step B: TFA (160 μL, 2.06 mmol, 8.0 equiv) was added to a solution oftert-butyl(4-(4-(4-(((1S,2S)-6-chloro-4-cyano-2-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)oxy)phenylsulfonamido)piperidin-1-yl)-4-oxobutyl)carbamate(210 mg, 0.26 mmol) in DCM (1.0 mL). The reaction mixture was stirredfor 18 h at rt, then concentrated under vacuum (azeotroping TFA withDCE) providing crude product (theoretical 0.26 mmol) as a white foam,which was used for the next step without purification. LCMS: retentiontime 3.24 minutes. MS (m/z): [M+H]⁺ 711.2.Step C: 1,4-Diisocyanatobutane (15.1 mg, 0.11 mmol, 0.43 equiv) wasadded to a solution ofN-(1-(4-aminobutanoyl)piperidin-4-yl)-4-(((1S,2S)-6-chloro-4-cyano-2-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)oxy)benzenesulfonamide(180 mg, 0.25 mmol) in DMF (0.8 mL) and Et₃N (175 μL, 1.26 mmol, 5equiv). The reaction mixture was stirred for 4 h at room temperaturediluted with H₂O/MeCN and purified by prep-HPLC with the followingconditions: Column, Atlantis Prep T3 OBD, 19*150 mm, 10 um; mobilephase, water (0.1% TFA) and CH₃CN (20.0% CH₃CN up to 80.0% in 40 min);Detector, UV 214 nm. Product eluted ˜77% MeCN. This procedure provided145 mg (86%) of the title compound as a white solid. LC/MS: retentiontime 4.37 minutes. MS (m/z): [M/2+H]⁺ 781.3.

Step D: 3M aq NaOH (185 μL, 0.55 mmol, 6.0 eq) was added to a solutionof(S,S,R)—N,N′-(1,1′-(6,13-dioxo-5,7,12,14-tetraazaoctadecane-1,18-dioyl)bis(piperidine-4,1-diyl))bis(4-(((1S,2S)-6-chloro-4-cyano-2-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)oxy)benzenesulfonamide)(145 mg, 0.9 mmol) in THF/methanol (0.9:0.1 mL). The reaction mixturewas stirred for 1 h at rt—complete by LC/MS. The reaction mixture wasdiluted in H₂O/MeCN and purified by prep-HPLC with the followingconditions: Column, Atlantis Prep T3 OBD, 19*150 mm, 10 um; mobilephase, water (0.1% TFA) and CH₃CN (10.0% CH₃CN up to 60.0% in 40 min);Detector, UV 214 nm. Product eluted ˜48% MeCN. This procedure provided108.8 mg (73%) of the title compound as a white solid. LC/MS: retentiontime 2.93 minutes. MS (m/z): (M/2+H]⁺ 685.3. ¹H NMR (Methanol-d4, 400MHz) δ 7.88 (d, J=8.9 Hz, 4H), 7.76 (d, J=1.9 Hz, 2H), 7.44 (s, 2H),7.31 (d, J=8.9 Hz, 4H), 6.06 (s, 2H), 4.24-4.16 (m, 1H), 3.84-3.70 (m,3H), 3.41-3.30 (m, 17H), 3.24-3.01 (m, 15H), 2.40-2.30 (m, 5H),1.85-1.76 (m, 1H), 1.71 (d, J=7.2 Hz, 4H), 1.46 (s, 5H), 1.28 (d, J=6.6Hz, 7H).

Example 173:4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)piperidin-4-yl]benzenesulfonamide

The title compound was prepared following the procedure from Example123. The residue purified by Column, Atlantis Prep T3 OBD, 19*150 mm, 10um; mobile phase, water (0.1% TFA) and CH₃CN (10.0% CH₃CN up to 60.0% in40 min); Detector, UV 214 nm. Product eluted—43% MeCN. This procedureprovided 28 mg (41%) of the title compound as a white solid. LCMS: ret.time 1.89 min. MS (m/z): [M/2+H]⁺ 687.3. ¹H NMR (Methanol-d4, 400 MHz) δ7.89 (d, J=9.0 Hz, 4H), 7.78-7.75 (m, 2H), 7.45-7.42 (m, 2H), 7.37-7.23(m, 4H), 6.11-6.02 (m, 2H), 3.80-3.67 (m, 8H), 3.61-3.47 (m, 10H), 3.32(dd, J=10.3, 7.5 Hz, 18H), 3.12 (d, J=8.8 Hz, 18H), 2.69-2.57 (m, 1H),2.37-2.28 (m, 1H), 2.08-1.94 (m, 6H), 1.88-1.74 (m, 2H), 1.53-1.39 (m,4H), 1.28 (d, J=6.6 Hz, 6H).

Example 174:4-([(1S,2S)-4,6-Dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide

Step A: (S)-tert-Butyl3-(4-hydroxyphenylsulfonamido)pyrrolidine-1-carboxylate (0.47 g, 1.37mmol, 1.1 eq),1-((R)-4-((1R,2R)-4,6-dichloro-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-methylpiperazin-1-yl)-2,2,2-trifluoroethanone(0.5 g, 1.25 mmol), and Ph₃P (0.49 g, 1.87 mmol, 1.5 eq) were dissolvedin THF (3 mL), the mixture heated at 40° C. for 15 minutes under N₂,then a solution of diisopropyl azodicarboxylate (0.39 mL, 2.0 mmol, 1.6eq) in THE (1.2 mL) was added dropwise within 15 minutes. The reactionmixture was stirred for 10 min (LCMS showed no starting aminoalcohol).The reaction mixture was concentrated under vacuum and purified bysilica gel chromatography with hexane:EtOAc (0 to 60%) providing 840 mg(93%) of product as a white foam. LCMS: ret time 3.96 min. MS (m/z):[M+H]⁺ 721.1.Step B: TFA (1.0 mL, 12.9 mmol, 11.7 eq) was added to a solution of(S)-tert-butyl(((1S,2S)-4,6-dichloro-1-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)phenylsulfonamido)pyrrolidine-1-carboxylate(800 mg, 1.1 mmol) in DCM (5.0 mL). The reaction mixture was stirred for16 h, the DCM removed by evaporation, and the residue was purified byprep-HPLC with the following conditions: Column, Atlantis Prep T3 OBD,50*250 mm, 10 um; mobile phase, water (0.1% TFA) and CH₃CN (30.0% CH₃CNup to 70.0% in 50 min); Detector, UV 214 nm. Product eluted ˜65% MeCN.Collected fractions were concentrated under vacuum, neutralized withsolid NaHCO₃ (pH 9), and extracted with 9:1 CHCl₃:IPA (3×40 mL).Combined organics were washed with brine (40 mL), dried over Na₂SO₄,filtered, and concentrated to afford 500 mg (73%) of product as a whitesolid. LCMS: ret time 2.95 min. MS (m/z): [M+H]⁺ 621.2.Step C: 2-(2-((tert-Butoxycarbonyl)amino)ethoxy)ethyl4-methylbenzenesulfonate (126 mg, 0.35 mmol, 1.1 eq),4-(((1S,2S)-4,6-dichloro-1-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)-N—((S)-pyrrolidin-3-yl)benzenesulfonamide(200 mg, 0.32 mmol) and K₂CO₃ (89 mg, 0.64 mmol, 2 eq) were mixed inMeCN (2.0 mL) and the mixture stirred at 55° C. for 16 h giving approx.50% conversion (LCMS). DMF (0.5 mL) was added and the slurry was stirredfor another 24 h at 60° C. giving complete conversion. The reactionmixture was filtered, the filtrates concentrated, and the residuepurified by silica gel column with DCM: MeOH (0 to 10%). The product 144mg (56%) was collected as a white foam. LCMS: ret time 3.3 min. MS(m/z): [M+H]⁺ 808.25.Step D: TFA (150 μL, 1.95 mmol, 11 eq) was added to a solution oftert-butyl(2-(2-((S)-3-(4-(((1S,2S)-4,6-dichloro-1-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)phenylsulfonamido)pyrrolidin-1-yl)ethoxy)ethyl)carbamate(145 mg, 0.18 mmol) in DCM (2 mL). The reaction mixture was stirred for15 h then concentrated under vacuum. The residue was dissolved in water(5 mL) and neutralized with solid NaHCO₃ (pH ˜8). The aqueous layer wasextracted with EtOAc (3×10 mL). The organic layer was dried over Na₂SO₄,filtered, and concentrated to afford 120 mg (95%) of desired product.LCMS: ret time 2.43 min. MS (m/z): [M+H]⁺ 708.2.Step E: A solution of 1,4-diisocyanatobutane (10 mg, 0.071 mmol, 0.42eq) in DMF (0.1 mL) was added to a solution ofN—((S)-1-(2-(2-aminoethoxy)ethyl)pyrrolidin-3-yl)-4-(((1S,2S)-4,6-dichloro-1-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)benzenesulfonamide(120 mg, 0.17 mmol) in DMF (0.4 mL). The reaction mixture was stirred atrt for 2 h, concentrated under vacuum, and the residue purified bysilica gel column DCM: 85DCM/15MeOH/5Et₃N (0 to 10%). Product eluted˜85% of polar solvent. 150 mg (theoretical 110 mg, not completely dry)of product was collected as a white foam. LCMS: ret time 3.56 min. MS(m/z): [M/2+H]⁺ 778.3.Step F: 3M aq NaOH (400 μL, 1.2 mmol, 17 eq) was added to a solution of(S,S,R)—N,N′-((3S,3′S′)-1,1′-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosane-1,20-diyl)bis(pyrrolidine-3,1-diyl))bis(4-(((1S,2S)-4,6-dichloro-1-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)benzenesulfonamide)(110 mg, 0.071 mmol) in MeOH (1 mL):THF (0.5 mL). The addition wasportionwise (130+130+240 μL) within 2 h, with LCMS monitoring of thereaction progress. After 2.5 h, the reaction was complete by LCMS. Thereaction was quenched with 4N HCl (pH ˜2), the volatiles removed undervacuum, and the residue purified by prep-HPLC with the followingconditions: Column, Atlantis Prep T3 OBD, 50*250 mm, 10 urn; mobilephase, water (0.1% TFA) and CH₃CN (20.0% CH₃CN up to 60.0% in 50 min);Detector, UV 214 nm. 127.7 mg (88%) was collected as a white solid.124.7 mg registered as NTX-0010630 tare: 4.9286. LCMS: ret time 1.89min. MS (m/z): [M/2+H]⁺ 682.3. ¹H NMR (Methanol-d4, 400 MHz) δ 7.87 (s,4H), 7.43-7.41 (m, 2H), 7.33 (d, J=9.0 Hz, 5H), 7.11-7.09 (m, 2H),6.07-6.04 (m, 2H), 3.77-3.70 (m, 8H), 3.70-3.62 (m, 3H), 3.55-3.49 (m,6H), 3.26-3.06 (m, 7H), 2.64 (s, 1H), 2.37-2.28 (m, 1H), 1.50-1.44 (m,3H), 1.28 (d, J=6.6 Hz, 6H).

Example 175:N¹,N¹⁴-Bis(2-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide

Step A: 2-(2-((tert-Butoxycarbonyl)amino)acetamido)acetic acid (84 mg,0.36 mmol, 1.5 eq),4-(((1S,2S)-4,6-dichloro-1-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)-N—((S)-pyrrolidin-3-yl)benzenesulfonamide(150 mg, 0.24 mmol), and HATU (183 mg, 0.48 mmol, 2 eq) were mixed inDMF (1 mL). Diisopropylethylamine (170 μL, 0.96 mmol, 4 eq) was addedand the mixture stirred for 15 minutes—complete by LCMS. The reactionmixture was concentrated under vacuum and the residue purified by silicagel column with DCM:MeOH (0 to 10%); 220 mg (>100%, not dry) of productwas collected as a slightly yellowish solid. LCMS: ret time 3.50 min. MS(m/z): [M+H]+ 835.2.Step B: TFA (300 μL, 3.9 mmol, 16 eq) was added to a solution oftert-butyl(2-((2-((S)-3-(4-(((1S,2S)-4,6-dichloro-1-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)phenylsulfonamido)pyrrolidin-1-yl)-2-oxoethyl)amino)-2-oxoethyl)carbamate(theoretical 200 mg, 0.24 mmol) in DCM (2 mL). The reaction mixture wasstirred at rt for 1 h —complete by LCMS. The volatiles were removed byevaporation and the residue dissolved in water (20 mL) and neutralizedwith solid NaHCO₃ (pH 9). The solution was extracted with EtOAc (2×20mL), then with 9:1 CHCl₃:IPA (2×20 mL) [compound mostly went to EtOAc].The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated to afford 173 mg (98%) of product as a tan foam. LCMS: rettime 2.89. MS (m/z): [M+H]⁺ 735.2.Step C: A solution of 1,4-diisocyanatobutane (14.5 mg, 0.10 mmol, 0.45eq) in DMF (0.14 mL) was added to a solution of2-amino-N-(2-((S)-3-(4-(((1S,2S)-4,6-dichloro-1-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)phenylsulfonamido)pyrrolidin-1-yl)-2-oxoethyl)acetamide(170 mg, 0.23 mmol) in DMF (0.5 mL). The reaction mixture was stirredfor 0.5 h—complete by LCMS. The reaction mixture was concentrated undervacuum and the residue purified by silica gel chromatography with DCM:8.5DCM/1.5MeOH/0.5Et₃N (0 to 65%). The product eluted at 60% of polarsolvent, 200 mg (theoretical 165 mg) collected as a white foam. LC/MS:ret time 3.28 minutes. MS (m/z): [M/2H]⁺ 782.3.Step D: 3M aq NaOH (100 μL, 0.3 mmol, 3 eq) was added to a solution ofN¹,N¹⁴-bis(2-((S)-3-(4-(((1S,2S)-4,6-dichloro-1-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)phenylsulfonamido)pyrrolidin-1-yl)-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecane-1,14-diamide(165 mg, 0.1 mmol) in THF:MeOH 0.6:0.07 mL. After 1 h, added additionalNaOH (300 μL) and MeOH (200 μL) in two portions over the next 2 hours.After 1 h the reaction was complete. The reaction was quenched with 4NHCl (pH ˜2), the volatiles removed under vacuum, and the residuepurified by prep-HPLC with the following conditions: Column, AtlantisPrep T3 OBD, 50*250 mm, 10 um; mobile phase, water (0.1% TFA) and CH₃CN(20.0% CH₃CN up to 60.0% in 50 min); Detector, UV 214 nm. 92 mg (48%)was collected as a white solid. 90.6 mg registered as NTX-0010628 tare:4.9269. LCMS: ret time 2.5 min. MS (m/z): [M/2+H]⁺ 709.3. ¹H NMR(Methanol-d4, 400 MHz) δ 7.91-7.80 (m, 4H), 7.43-7.37 (m, 2H), 7.30 (s,4H), 7.16-7.10 (m, 2H), 6.07-6.00 (m, 2H), 3.94-3.89 (m, 3H), 3.79 (d,J=4.9 Hz, 5H), 3.59-3.50 (m, 4H), 3.13 (s, 14H), 1.53-1.45 (m, 4H), 1.25(d, J=6.6 Hz, 6H).

Example 176:4-([(1S,2S)-4-Cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-Ill-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-4-cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide

Step A: 3-(2-Bromo-4-methylphenyl)propanoic acid (2.4 g, 9.9 mmol) wasdissolved in DCM (12 mL) and DMF (0.1 mL, 1.3 mmol, 0.13 eq). Oxalylchloride (1.7 mL, 19.7 mmol, 2 eq) was added dropwise over 7 minutes.The reaction mixture was stirred at rt under N₂ for 1.5 h (LCMS showedno starting material). The reaction mixture was concentrated undervacuum to ⅓ of original volume and added to a precooled suspension ofAlCl₃ (1.7 g, 12.8 mmol, 1.3 eq) in DCM (10 mL) over 5 minutes, keepinginternal temperature <5° C. The reaction mixture was stirred at 3-5° C.for 20 minutes before the ice bath was removed and mixture stirred foranother 20 minutes—complete by LCMS. The reaction mixture was quenchedby slow addition of cold 3M aq HCl (20 mL) under cooling. The solutionwas extracted with DCM (3×25 mL). The combined organic layers werewashed with brine (2×25 mL), dried over Na₂SO₄, filtered, andconcentrated under vacuum. The residual solid was suspended in hexaneand collected by filtration—product 2.0 g (90%), white solid; LCMS, NMRare good. The filtrates were purified by silica gel chromatographyHexane:EtOAc (0 to 15%) to afford 0.1 g of product. LCMS: ret time 2.75minutes. MS (m/z): [M+H]⁺ 225.0.Step B: To 4-bromo-6-methyl-2,3-dihydro-1H-inden-1-one (2.1 g, 9.3 mmol)in methanol (23 mL) was added NaBH₄ (320 mg, 8.45 mmol, 0.9 eq),becoming homogenous with addition. After 10 min, the reaction wascomplete (LCMS) and the solvent was evaporated. The residue was slurriedin 40 mL of water and extracted with EtOAc (3×35 mL). The combinedorganic layers were washed with brine (2×30 mL), dried over Na₂SO₄,filtered, and concentrated to 2.1 g (99%) of white solid. LCMS and NMRare good. The crude was used directly in the next step. LCMS: ret. time2.49 minutes. MS (m/z): [M−H₂O+H]⁺209.0.Step C: 4-Bromo-6-methyl-2,3-dihydro-1H-inden-1-ol (2.1 g, 9.2 mmol)suspended in toluene (10 mL), pTsOH.H₂O (175 mg, 0.92 mmol, 0.1 eq) wasadded at room temperature and mixture heated to 90° C. (internal). Thereaction mixture was stirred at 90° C. for 20 min—complete by LCMS. Uponcooling EtOAc (30 mL) was added and the resulting solution washed withbrine (2×15 mL). The organic phase was dried over Na₂SO₄, filtered, andconcentrated under vacuum to afford 1.8 g of crude product as ayellowish oil. NMR and LCMS showed mixture of 2 compounds which wereseparated by silica gel chromatography with hexane (2 long columns).Desired product—indene, eluted first, providing 600 mg (31%) as acolorless liquid. Ret time 3.6 minutes, no ionization, NMR confirmedstructure.Step D: 7-Bromo-5-methyl-1H-indene (0.6 g, 2.86 mmol) was dissolved inDCM (18 mL) and treated with a solution of pyridine 1-oxide (1.35 g,14.3 mmol, 5 eq) in DCM (10 mL), followed by (S,S)-Jacobsen catalyst(Sigma-Aldrich 404454, CAS 135620-04-1). The mixture was cooled to 0° C.and stirred for 15 minutes. mCPBA (0.98 g, 5.72 mmol, 2 eq) was added in3 portions over 10 minutes. The reaction mixture was stirred at 0° C.for another hour (complete by TLC). The reaction mixture was quenchedwith 3M aq NaOH (8 mL), the organic layer separated, and the aqueouslayer extracted with hexane (2×20 mL). The combined organic layers werewashed with water (20 mL) and brine (20 mL), dried over Na₂SO₄,filtered, and concentrated under vacuum. The residue was purified bysilica gel chromatography with hexane:DCM (0 to 40%) to afford 320 mg(50%) of scalemic epoxide, used for the next step without resolution.Step E: 5-Bromo-3-methyl-6,6a-dihydro-1aH-indeno[1,2-b]oxirene (300 mg,1.33 mmol) [scalemic material from epoxidation step] and (R)-tert-butyl2-methylpiperazine-1-carboxylate (318 mg, 1.59 mmol, 1.2 eq) were mixedin MeCN (4 mL) and heated at 65° C. for 16 h. The reaction mixture wasconcentrated under vacuum and the residue purified by silica gelchromatography with hexane:EtOAc (0 to 40%): 260 mg (46%) of product wascollected as a tan foam. NMR showed presence of other diastereomer(˜10%). LCMS: ret time 2.36 min. MS (m/z): [M+H]⁺ 425.1.Step F: (R)-tert-Butyl4-((1R,2R)-4-bromo-2-hydroxy-6-methyl-2,3-dihydro-1H-inden-1-yl)-2-methylpiperazine-1-carboxylate(0.2 g, 0.47 mmol),2,2,2-trifluoro-N-(2-(2-(2-(4-hydroxyphenylsulfonamido)ethoxy)ethoxy)ethyl)acetamide(0.2 g, 0.51 mmol, 1.1 eq) and Ph₃P (0.18 g, 0.7 mmol, 1.5 eq) weredissolved in THF (1.2 mL) and the mixture heated at 40° C. for 15minutes under N₂. A solution of diisopropyl azodicarboxylate (0.15 mL,0.75 mmol, 1.6 eq) in THF (0.4 mL) was added dropwise within 5 minutes.The reaction mixture was stirred for 20 more minutes—complete by LCMS.The reaction mixture was concentrated under vacuum and the residue waspurified by silica gel chromatography with hexane:EtOAc (0 to 70%) toafford 0.35 g (92%) of product as a white foam. NMR and LCMS showedimpurity of other diastereomer which came from the prev. step. LCMSmajor diastereomer: ret time 3.44 min. MS (m/z): [M+H]⁺ 807.2.Step G: (R)-tert-Butyl4-((1S,2S)-4-bromo-6-methyl-1-(4-(N-(2-(2-(2-(2,2,2-trifluoroacetamido)ethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-2,3-dihydro-1H-inden-2-yl)-2-methylpiperazine-1-carboxylate(0.35 g, 0.43 mmol) and Zn(CN)₂ (30.4 mg, 0.26 mmol, 0.6 eq) weredissolved in NMP (1.5 mL), N2 bubbled through solution, then (Ph₃P)₄Pd(50 mg, 0.04 mmol, 0.1 eq) was added. The reaction mixture was stirredunder N₂ at 100° C. for 3 h. The reaction mixture was diluted in water(10 mL) and the suspension was extracted with EtOAc (3×15 mL). Thecombined organics were washed with brine (3×7 mL), dried with Na₂SO₄,concentrated under vacuum, and the residue purified by silica gelchromatography with hexane:EtOAc (0 to 100%), 0.25 g (77%) of productwas collected as a white foam. LCMS: major diastereomer 3.13 minutes. MS(m/z): [M+H]⁺ 754.3.Step H: 3M aq NaOH (300 μL, 0.9 mmol, 2.7 eq) was added to a solution of(R)-tert-butyl 4-((1S,2S)-4-cyano-6-methyl-1-(4-(N-(2-(2-(2-(2,2,2-trifluoroacetamido)ethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-2,3-dihydro-1H-inden-2-yl)-2-methylpiperazine-1-carboxylate (250 mg, 0.33 mmol) in MeOH (1.2 mL):THF (0.3 mL). The reactionmixture was stirred for 1.5 h at rt—complete by LCMS. The reactionmixture was concentrated under vacuum and the residue dissolved inMeCN/H₂O and purified by prep-HPLC with the following conditions:Column, Atlantis Prep T3 OBD, 50*250 mm, 10 um; mobile phase, water(0.1% TFA) and CH₃CN (25.0% CH₃CN isochratic for 10 min then up to 60.0%in 20 min); Detector, UV 214 nm. 245 mg (96%) was collected as a whitesolid. LCMS: ret time 2.43 min. MS (m/z): [M+H]⁺ 658.3.Step I: Triethylamine (100 μL, 0.72 mmol, 4.3 eq) was added to asolution of (R)-tert-butyl4-((1S,2S)-1-(4-(N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-4-cyano-6-methyl-2,3-dihydro-1H-inden-2-yl)-2-methylpiperazine-1-carboxylate2,2,2-tri fluoroacetate (130 mg, 0.17 mmol, 1 eq) in DMF (0.5 mL). Asolution of 1,4-diisocyanatobutane (9.5 mg, 0.067 mmol, 0.4 eq) in DMF(0.1 mL) was added. The reaction mixture was stirred for 20 min atrt—complete by LCMS. The reaction mixture was concentrated under vacuumand the residue purified by silica gel chromatographyDCM:85DCM/15MeOH/5Et₃N (0 to 90%). 150 mg of product was collected (notcompletely dry) as a white solid. LCMS: ret time 3.64 minutes. MS (m/z):[M/2+H]⁺ 728.4.Step J: (2R,2′R)-di-tert-Butyl4,4′-((1S,1′S,2S,2′S)-(((((26-(hydrosulfonylamino)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl)amino)sulfonyl)bis(4,1-phenylene))bis(oxy))bis(6-cyano-4-methyl-2,3-dihydro-1H-indene-2,1-diyl))bis(2-methylpiperazine-1-carboxylate)(100 mg, 0.68 mmol) was dissolved in DCM (0.5 mL) then TFA (200μ, 2.61mmol, 38 eq) was added. The reaction mixture was stirred for 2h—complete by LCMS. The reaction mixture was concentrated and theresidue purified by prep-HPLC with the following conditions: Column,Atlantis Prep T3 OBD, 50*250 mm, 10 um; mobile phase, water (0.1% TFA)and CH₃CN (20.0-60.0% CH₃CN); Detector, UV 214 nm. 84 mg (72%) wascollected as a white solid. LCMS: ret time 2.36 min. MS (m/z): [M+H]⁺628.3. ¹H NMR (Methanol-d4, 400 MHz) δ 7.85 (d, J=9.0 Hz, 4H), 7.51 (s,2H), 7.30 (t, J=5.9 Hz, 7H), 6.05-6.00 (m, 2H), 3.72-3.64 (m, 1H), 3.55(dd, J=6.2, 1.6 Hz, 9H), 3.49 (td, J=5.5, 2.8 Hz, 9H), 3.39-3.30 (m,5H), 3.20-3.00 (m, 19H), 2.68-2.58 (m, 1H), 2.31 (s, 9H), 1.45 (s, 4H),1.28 (d, J=6.6 Hz, 6H).

Example 177:3-(2-{2-[(3S)-3-(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}(2,3,5,6-²H₄)benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}(2,3,5,6-²H₄)benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}(1,1,2,2,3,3,4,4-²H₈)butyl)urea

Step A: 4-Bromophenol-2,3,5,6-th (300 mg, 1.69 mmol, 1 eq) was dissolvedin acetonitrile (5 mL). Powdered potassium carbonate (0.39 g, 2.8 mmol,1.6 eq) was added while stirring, followed by dropwise addition ofbenzyl bromide (0.24 mL, 2.0 mmol, 1.2 eq). The mixture was vigorouslystirred under nitrogen over weekend (after 6 h˜90% conversion). Thereaction mixture was filtered and filtrates concentrated under vacuum toafford crude product as a white solid, used for in next step withoutpurification. LCMS: ret.time 3.52 min, no ionization.Step B: Crude 1-(benzyloxy)-4-bromobenzene-2,3,5,6-d₄ (450 mg, 1.69mmol, 1 eq), Pd₂(dba)₃ (38.4 mg, 0.042 mmol, 0.025 eq), and xantphos(48.6 mg, 0.084 mmol, 0.05 eq) were dissolved in dioxane (6.7 mL) andiPr₂EtN (0.58 mL, 3.38 mmol, 2 eq). The solution was degassed with N2,the vial sealed, and BnSH (0.2 mL, 1.69 mmol, 1 eq) added. The reactionmixture was stirred at 90° C. for 5 h, concentrated under vacuum, andthe residue purified by silica gel column with hexane:EtOAc (0 to 10%)to afford 310 mg (60%) of product as a white solid. LCMS: ret time 3.84min. MS (m/z): [M+H]⁺ 311.5.Step C: Benzyl(4-(benzyloxy)phenyl-2,3,5,6-d₄)sulfone (310 mg, 1 mmol, 1eq) was suspended in AcOH/H₂O (7.5:2.5 mL). NCS (399 mg, 3 mmol, 3 eq)was added and reaction mixture stirred at rt for 2 h—complete by LCMS.The reaction mixture was diluted in EtOAc (50 mL) and washed with satNaHCO₃ (2×15 mL), brine (20 mL). The organic phase was dried overNa₂SO₄, filtered, and concentrated to afford crude product (286 mg,theoretical) as a white solid. The material was used for the next stepwithout purification. LCMS: ret time 3.34 min, no ionization.Step D: To a solution of crude 4-(benzyloxy)benzenesulfonylchloride-2,3,5,6-d₄ (theoretical 0.29 g, 1.0 mmol) in DCM (2 mL) wasadded solution of (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (0.23g, 1.2 mmol, 1.2 equiv) in DCM (1 mL) then Et₃N (0.17 mL, 1.2 mmol, 1.2eq) was added. The reaction mixture was stirred at rt for 20minutes—complete by LC/MS. The reaction mixture was concentrated undervacuum and the residue purified by silica gel chromatography withhexane:EtOAc (0 to 50%) to afford 320 mg (73%) of product as a whitesolid. LCMS: retention time 3.14 minutes. MS (m/z): [M+Na]⁺ 459.1.Step E: tert-Butyl(S)-3-((4-(benzyloxy)phenyl)sulfonamido-2,3,5,6-d₄)pyrrolidine-1-carboxylate(320 mg, 0.73 mmol) and Pd (10% on carbon, 50% wet, 100 mg, 0.05 mmol)were mixed in MeOH (3.7 mL). Vac/H₂ cycles were performed and thereaction slurry was stirred under H₂ at room temperature for 2.5h—complete by LCMS. The reaction mixture was filtered through a pad ofCelite 545, and eluted with EtOAc. The filtrate was concentrated toafford 250 mg (99%) of product as a white foam. LCMS: ret time 2.09 min.MS (m/z): [M+Na]⁺ 369.1.Step F:1-((R)-4-((1R,2R)-4-Bromo-6-chloro-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-methylpiperazin-1-yl)-2,2,2-trifluoroethanone(289 mg, 0.66 mmol, 1 eq),boc-(S)-3-((4-hydroxyphenyl)sulfonamido-2,3,5,6-d₄)pyrrolidine (250 mg,0.72 mmol, 1.1 eq) and triphenylphosphine (257 mg, 0.98 mmol, 1.5 eq)were mixed in THF (2.0 mL) and stirred at 40° C. for 15 minutes underN₂. A solution of DIAD (0.2 mL, 1.07 mmol, 1.6 eq) in THF (0.7 mL) wasadded dropwise within 5 minutes. The reaction mixture was stirred for 10min—complete by LCMS. The reaction mixture was concentrated under vacuumand the residue purified by silica gel chromatography with hexane:EtOAc(0 to 50%) affording 290 mg (58%) of product as a white foam. LCMS: rettime 4.05 min. MS (m/z): [M+H]⁺ 769.15.Step G: The bromide (270 mg, 0.35 mmol, 1 eq), Zn(CN)₂ (23 mg, 0.19mmol, 0.55 eq), Zn (˜4 mg), Pd₂(dba)₃ (96 mg, 0.1 mmol, 0.3 eq), anddppf (116 mg, 0.21 mmol, 0.6 eq) were dissolved in 3:1 dioxane:H₂O (3.5mL) and the reaction mixture stirred at 80° C. under N₂ for 2.5 h—complete by LCMS. The reaction mixture was diluted in EtOAc (40 mL) andwashed with brine (15 mL). The organic phase was dried over Na₂SO₄,filtered, concentrated, and the residue purified by silica gel columnwith hexane:EtOAc (0 to 60%) affording 205 mg (82%) of product as anorange foam.Step H: TFA (0.2 mL, 2.61 mmol, 9.3 equiv) was added to a solution of(S)-tert-butyl3-(4-(((1S,2S)-4-chloro-6-cyano-1-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)phenyl-da-sulfonamido)pyrrolidine-1-carboxylate(0.2 g, 0.28 mmol) in DCM (1.4 mL), The reaction mixture was stirred atrt for 16 h—complete by LCMS. The reaction mixture was concentratedunder vacuum and the residue purified by prep-HPLC with the followingconditions: Column, Atlantis Prep T3 OBD, 50*250 mm, 10 um; mobilephase, water (0.1% TFA) and CH₃CN (30.0% CH₃CN up to 70.0% in 50 min);Detector, UV 214 nm. Product eluted ˜58% MeCN. MeCN removed undervacuum, the aq phase neutralized with solid NaHCO₃ and extracted withEtOAc (3×25 mL). Organic phases dried over Na₂SO₄, filtered andconcentrated to afford 136 mg (80%) of product. LCMS: ret time 2.61 min.MS (m/z): [M++H]⁺ 616.2.Step I: 2-(2-((tert-Butoxycarbonyl)amino)ethoxy)ethyl4-methylbenzenesulfonate (102 mg, 0.29 mmol, 1.3 eq),4-(((1S,2S)-4-chloro-6-cyano-1-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)-N—((S)-pyrrolidin-3-yl)benzene-d₄-sulfonamide(136 mg, 0.22 mmol), and K₂CO₃ (61 mg, 0.44 mmol, 2 eq) were mixed inMeCN (1.7 mL) and stirred at 50° C. for 20 h—complete consumption ofamine by LCMS. The reaction mixture was diluted with EtOAc, filtered,and concentrated under vacuum. The residue was purified by silica gelchromatography with hexane:EtOAc (50 to 80%) then with DCM:MeOH (0 to6%) providing 128 mg (73%) of product as a white solid. LCMS: ret time3.0 min. MS (m/z): [M+H]⁺ 803.3.Step J: TFA (100 μL, 1.27 mmol, 8 eq) was added to a solution oftert-butyl(2-(2-((S)-3-((4-(((1S,2S)-6-chloro-4-cyano-2-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl)sulfonamido-2,3,5,6-d₄)pyrrolidin-1-yl)ethoxy)ethyl)carbamate(128 mg, 0.16 mmol) in DCM (1 mL). The reaction mixture was stirred atrt for 5 h—complete by LCMS. The reaction mixture was concentrated. Theresidue was dissolved in water (3 mL), neutralized with solid NaHCO₃,and extracted with 9:1 CHCl₃:IPA.(3×5 mL). The combined organics werewashed with brine, dried over Na₂SO₄, filtered, and concentrated undervacuum to afford 108 mg (97%) of product as a white foam. LCMS:retention time 2.27 minutes. MS (m/z): [M+H]⁺ 703.3.Step K: Butane-1,4-diamine dihydrochloride (300 mg, 1.86 mmol) and CDI(930 mg, 5.7 mmol, 3 eq) were dissolved in MeCN (3.5 mL, 0.5M) andsuspension was cooled to 0° C., then diisopropylethylamine (0.97 mL, 5.6mmol, 3 eq) was added. The reaction mixture was allowed to warm to rtand stirred for 1.5 h. The reaction mixture was quenched with H₂O (2 mL)and filtered, the solids washed with 4:1 MeCN:H₂O (3 mL) then with MeCN(4×2 mL), dried under vacuum to provide 400 mg (78%) of product as awhite solid.N—((S)-1-(2-(2-aminoethoxy)ethyl)pyrrolidin-3-yl)-4-(((1S,2S)-6-chloro-4-cyano-2-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)oxy)benzene-d4-sulfonamide(100 mg, 0.14 mmol, 2.2 eq) andN,N′-(butane-d₈-1,4-diyl)bis(1H-imidazole-1-carboxamide) (18.3 mg, 0.065mmol) were mixed in THF (0.6 mL) and stirred at 60° C. for 1.5h—complete by LCMS. The reaction mixture was concentrated under vacuumand the residue purified by silica gel column DCM: 85/15/5 DCM/MeOH/Et₃N(0 to 70%) to afford product as a tan foam. LCMS: ret time 3.13 min. MS(m/z): [M/2+H]⁺ 777.3.Step L: Sodium hydroxide (3M NaOH(aq), 100 μL, 0.3 mmol, 4.7 eq) wasadded to a solution of protected dimer (100 mg, 0.065 mmol) in THF:MeOH(0.38:0.26 mL). The reaction mixture was stirred for 1 h (LCMS showedonly sm). Additional 3M aq NaOH (200 μL, 0.6 mmol, 9.4 eq) was added tothe reaction mixture in 2 portions within 1 hour at which point thereaction complete by LCMS. The reaction mixture was neutralized with 4NHCl (0.3 mL, 1.2 mmol, 1.3 eq relative to NaO H), the volatiles removedunder vacuum, and the residue purified by prep-HPLC with the followingconditions: Column, Atlantis Prep T3 OBD, 50*250 mm, 10 um; mobilephase, water (0.1% TEA) and CH₃CN (25.0% CH₃CN up to 60.0% in 50 min);Detector, UV 214 nm. Lyophilization provided 64 mg (73%) of the titlecompound as a white solid. LCMS: ret time 1.95 min. MS (m/z): 681.3[M/2+H]⁺. ¹H NMR (Methanol-d4, 400 MHz) δ 7.77 (d, J=1.9 Hz, 2H), 7.44(d, J=0.9 Hz, 2H), 6.08 (d, J=5.9 Hz, 2H), 3.74 (t, J=4.9 Hz, 13H), 3.52(t, J=5.4 Hz, 6H), 3.23-2.97 (m, 9H), 2.63 (t, J=12.0 Hz, 1H), 2.34 (t,J=9.8 Hz, 2H), 1.28 (d, J=6.6 Hz, 6H).

Example 178:3-(2-{2-[(3S)-3-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}(1,1,2,2,3,3,4,4-²H₈)butyl)urea

The title compound was prepared from INT-M5E utilizing the sameprocedures in Example 177. LCMS: ret time 1.9 min. MS (m/z) [M/3+H]⁺452.1. ¹H NMR (Methanol-d4, 400 MHz) δ 7.89 (d, J=8.9 Hz, 4H), 7.79-7.76(m, 2H), 7.47-7.41 (m, 2H), 7.35 (d, J=9.0 Hz, 5H), 6.11-6.04 (m, 2H),4.04-3.87 (m, 1H), 3.74 (d, J=4.9 Hz, 9H), 3.52 (s, 4H), 3.14 (s, 15H),2.68-2.58 (m, 2H), 2.39-2.27 (m, 3H), 2.06-1.88 (m, 2H), 1.28 (d, 6.6Hz, 7H).

Example 179:(1S,2S)-1-(4-{[(3S)-[2-(2-{[(4-{[2-{2-[(3S)-3-(4-≡[(1S,2S)-4-carboxy-6-chloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)-1-hydroxy-1λ⁴-pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)carbamoyl]amino}ethoxy)ethyl]-1-hydroxy-1λ⁴-pyrrolidin-3-yl]sulfamoyl}phenoxy)-6-chloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-indene-4-carboxylicacid

Hydrogen peroxide (3%, 0.1 mL, 87.9 mmol, 2.4 eq) was added to Example132 (50 mg, 37.1 mmol), followed by water (0.2 mL). The suspension wassonicated for 1 hour. The reaction mixture diluted with 1M HCl,filtered, and purified by prep-HPLC with the following conditions:Column, Atlantis Prep T3 OBD, 50*250 mm, 10 um; mobile phase, water(0.1% TFA) and CH₃CN (25.0% CH₃CN up to 50.0% in 50 min); Detector, UV214 nm. Lyophilization provided the title diacid di-N-oxide (NMR, HPLC).MS (m/z): 708.2 [M/2+H]⁺, 472.5 [M/3+H]⁺. ¹H NMR (Methanol-d4, 400 MHz)δ 7.87-7.72 (m, 3H), 7.59 (s, 2H), 7.25 (dd, J=14.4, 5.5 Hz, 6H), 5.93(d, J=5.6 Hz, 2H), 4.16 (s, 1H), 4.00-3.75 (m, 14H), 3.02 (s, 12H), 2.54(s, 1H), 2.40 (s, 1H), 2.23 (s, 1H), 1.39 (s, 3H), 1.25-1.13 (m, 6H).

Example 180: Cell-Bused Assay of NHE-3 Activity (Pre-IncubationInhibition)

Rat and human NHL-3-mediated Na⁺-dependent H⁺ antiport was measuredusing a modification of the pH sensitive dye method originally reportedby Paradiso (Proc. Natl. Acad. Sci. USA. (1984) 81(23): 7436-7440).PS120 fibroblasts stably expressing human NHE3 and NHERF2 were obtainedfrom Mark Donowitz (Baltimore, Md.). Opossum kidney (OK) cells wereobtained from the ATCC and propagated per their instructions. The ratNHE-3 gene (GenBank M85300) was introduced into OK cells viaelectroporation, and cells were seeded into 96 well plates and grownovernight. Medium was aspirated from the wells then incubated for 30 minat 37° C. with NH₄Cl-HEPES buffer (20 mM NH₄Cl, 80 mM NaCl, 50 mM HEPES,5 mM KCl, 2 mM CaCl₂), 1 mM MgCl₂, pH 7.4) containing 5 μM BCECF-AM.Cells were washed once with Ammonium free, Na⁺-free HEPES (100 mMcholine, 50 mM HEPES, 10 mM glucose, 5 mM KCl, 2 mM CaCl₂), 1 mM MgCl₂,pH 7.4) and incubated in the same buffer for 10 minutes at roomtemperature to lower intracellular pH with 0-30 μM test compound. Afterincubation, NHE-3-mediated recovery of neutral intracellular pH wasinitiated by addition of Na-HEPES buffer containing 0.4 uM ethylisopropyl amiloride (EIPA, a selective antagonist of NHE-1 activity thatdoes not inhibit NHE-3). Changes in intracellular pH were monitoredusing a FLIPR Tetra® (Molecular Devices, Sunnyvale, Calif.) byexcitation at LA 439 to 505 nm, and measuring BCECF fluorescence atλ_(em) 538 nm. The initial rate of the fluorescence ratio change wasused as a measure of NHE-mediated Na⁺/H⁺ activity, and reported as thechange in fluorescence ratio per minute. Initial rates were plotted asthe average of 2 or more replicates, and pIC₅₀ values were estimatedusing GraphPad Prism.

TABLE 2 Data for example in human Preincubation assay: Result pIC₅₀Range % inhibition range A NHE3 pIC₅₀ < 6 NHE3 <40% B NHE3 pIC₅₀ 6-740-70% C NHE3 pIC₅₀ > 7   >70% human Preincubation Example pIC50 %Inhibition 1 C C 2 C C 3 C C 4 C B 5 C B 6 A A 7 C C 8 A A 9 C A 10 C B11 C C 12 C A 13 A A 14 A B 15 B C 16 C B 17 C C 18 C B 19 A A 20 A A 21C A 22 C C 23 C C 24 C C 25 C C 26 C C 27 C C 28 C C 29 C C 30 C C 31 CC 32 C C 33 C C 34 C C 35 C C 36 C C 37 C B 38 A A 39 C A 40 A A 41 C C42 C C 43 C C 44 C C 45 C C 46 C C 47 C C 48 B B 49 B C 50 C B 51 C B 52C C 53 C C 54 C C 55 C C 56 C C 57 C C 58 C C 59 C C 60 C C 61 C C 62 CC 63 C B 64 A A 65 A A 66 A A 67 B C 68 C C 69 C C 70 C C 71 A B 72 C C73 B C 74 A C 75 B B 76 C C 77 A C 78 C C 79 C C 80 B B 81 C C 82 C B 83C C 84 C C 85 C C 86 C C 87 C C 88 C C 89 C C 90 C C 91 C C 92 C C 93 CC 94 C C 95 C C 96 C C 97 C C 98 C C 99 C C 100 C C 101 C C 102 C C 103C C 104 C C 105 C C 106 C C 107 C C 108 C C 109 C C 110 C C 111 C C 112C C 113 C C 114 C C 115 C C 120 C C 121 C B 122 C C 123 C C 124 C C 126C C 127 C C 128 A A 129 A A 130 C B 131 C C 132 C C 133 C C 134 C C 135C C 136 C C 137 C C 142 C C 143 C C 146 C C 154 C C

Example 181: Cell-Based Assay of NHE-3 Activity (Persistent Inhibition)

The ability of compounds to inhibit human and rat NHE-3-mediatedNa′-dependent H⁺ antiport after application and washout was measuredusing a modification of the pH sensitive dye method described above.PS120 fibroblasts stably expressing human NHE3 and NHERF2 were obtainedfrom Mark Donowitz (Baltimore, Md.). Opossum kidney (OK) cells wereobtained from the ATCC and propagated per their instructions. The ratNHE-3 gene was introduced into OK cells via electroporation, and cellswere seeded into 96 well plates and grown overnight. Medium wasaspirated from the wells, cells were washed once with NaCl-HEPES buffer(100 mM NaCl, 50 mM HEPES, 10 mM glucose, 5 mM KCl, 2 mM CaCl₂), 1 mMMgCl₂, pH 7.4), then overlayed with NaCl-HEPES buffer containing 0-30 μMtest compound. After a 60 min incubation at room temperature, the testdrug containing buffer was aspirated from the cells. Followingaspiration, cells were washed once with NaCl-HEPES buffer without drug,then incubated for 30 min at 37° C. with NH₄Cl-HEPES buffer (20 mMNH₄Cl, 80 mM NaCl, 50 mM HEPES, 5 mM KCl, 2 mM CaCl₂), 1 mM MgCl₂, pH7.4) containing 5 μM BCECF-AM. Cells were washed once with Ammoniumfree, Na⁺-free HEPES (100 mM choline, 50 mM HEPES, 10 mM glucose, 5 mMKCl, 2 mM CaCl₂), 1 mM MgCl₂, pH 7.4) and incubated in the same bufferfor 10 minutes at room temperature to lower intracellular pH.NHE-3-mediated recovery of neutral intracellular pH was initiated (10min after compound washout) by addition of Na-HEPES buffer. For the ratNHE3 assay, the Na-HEPES buffer contained 0.4 μM ethyl isopropylamiloride (EIPA, a selective antagonist of NILE-1 activity that does notinhibit NHE-3). Changes in intracellular pH were monitored using a FLIPRTetra® (Molecular Devices, Sunnyvale, Calif.) by excitation at λ_(ex)439 to 505 nm, and measuring BCECF fluorescence at λ_(em) 538 nm. Theinitial rate of the fluorescence ratio change was used as a measure ofNHE-mediated Na⁺/H⁺ activity, and reported as the change in fluorescenceratio per minute. Initial rates were plotted as the average of 2 or morereplicates, and pIC₅₀ values were estimated using GraphPad Prism.

TABLE 3 Data for example in human Persistence assay: % inhibition ResultpIC₅₀ Range range A NHE3 pIC₅₀ < 6 NHE3 < 40% B NHE3 pIC₅₀ 6-7 40-70% CNHE3 pIC₅₀ > 7   >70% human Persistence Example pIC50 % inhibition 1 C B2 C C 3 C C 4 C B 5 C C 6 A A 7 C C 8 A A 9 B B 10 C C 11 C C 12 B B 13A A 14 A A 15 A A 16 C B 17 C C 18 C B 19 A A 20 A A 21 A C 22 C C 23 CC 24 C C 25 C C 26 C C 27 C C 28 C C 29 C C 30 C C 31 C C 32 C C 33 C C34 C C 35 C C 36 C C 37 C B 38 A A 39 C A 40 A A 41 C C 42 C C 43 C C 44B C 45 C C 46 C C 47 C C 48 B C 49 C C 50 C B 51 C B 52 C C 53 C C 54 CB 55 C C 56 C C 57 C C 58 C C 59 C C 60 C C 61 C C 62 A A 63 B B 64 A A65 A A 66 A A 67 B B 68 C C 69 B C 70 C C 71 A B 72 B C 73 A B 74 A A 75A A 76 A A 77 A A 78 C C 79 B C 80 B B 81 B C 82 B C 83 B C 84 C C 85 CC 86 C C 87 C C 88 C C 89 C C 90 B C 91 C C 92 C C 93 C C 94 C C 95 C C96 C C 97 C C 98 C C 99 B C 100 C C 101 C B 102 C C 103 C C 104 C C 105C C 106 C C 107 C C 108 C C 109 C C 110 C C 111 C C 112 C C 113 C C 114C C 115 C C 120 C C 121 C A 122 C C 123 C C 124 B C 126 C B 127 C A 128C A 129 C A 130 B C 131 B C 132 C C 133 C C 134 C C 135 C C 136 C C 137C C 142 C C 143 C C 146 C A 154 C C

Example 182: Sustained Inhibition of Apical Acid Secretion in HumanOrganoid Monolayer Cell Cultures

Basal media (BM) consisted of advanced DMEM/F12 containing 10 mM HEPES(Invitrogen, 15630-080), 1:100 Glutamax (Invitrogen, 35050-061), and1:100 penicillin/streptomycin (Invitrogen, 15140-122). Supplementedbasal media (SBM) contained 1:100 N2 (Invitrogen, 17502-048), 1:50 B27(Invitrogen, 12587-010), 1 mM N-acetylcysteine (Sigma, A9165), and 10 nM[Leu15]-gastrin I (Sigma, G9145). Growth factors used included 50 ng permL mouse EGF (Peprotech, 315-09), 100 ng per mL mouse noggin (Peprotech,250-38), 500 ng per mL human R-spondin 1 (R&D, 4645-RS), 100 ng per mLmouse Wnt-3a (R&D, 1324-WN), 20 μM Y-27632 (Tocris, 1254), 10 mMnicotinamide (Sigma, N0636), 500 nM A83-01 (Tocris, 2939), 10 μMSB202190 (Tocris, 1264). Transwells were 0.4 μm pore polyester membrane24-well Transwell inserts (Corning). Cultures were incubated at 37° C.in 5% C07.

Human ileum organoids were cultured in WENRNAS (Wnt, EGF, noggin,R-spondin 1, Nicotinamide, A83-01, SB202190) and typically grown for7-12 days before being used to plate monolayer cultures. On day 0,organoid cultures embedded in Matrigel were treated with TrypLE Expressto break organoids into small pieces and/or single cells. The cells wereresuspended to 0.5×10⁶ cells/mL in SBM containing WENRAY (Wnt, EGF,noggin, R-spondin 1, A83-01, Y-27632). Following this step, 200 μL ofcell suspension was plated into the apical side of a 24-well Transwell(100,000 cells/well) and 600 μL of SBM with WENRAY was added to thebasolateral side. Ileum cells were differentiated with ENRA (EGF,noggin, R-spondin 1, A83-01) on day 3. The color of apical compartmentturns from pink or orange to yellow due to the increase in NHE3expression after differentiation.

Each human ileum monolayer culture well was washed twice with fresh SBMon the apical side on day 6 before compound dosing. All compound stockswere 10 mM dissolved in DMSO. Each compound stock was individually mixedwith fresh SBM to reach final compound concentration 1 μM and dosed onlyon the apical side of the monolayer (total volume 200 μl). DMSO at theequivalent concentration was used as the vehicle control. Duplicatewells were dosed for each compound. On day 8, apical media pH wasmeasured by pH electrode, to determine the ability of example compoundsto produce sustained inhibition of NHE3 activity in a human monolayerculture system by preventing proton secretion into the apicalcompartment. Each of the duplicate apical pH values for each examplecompound was compared to the average of the DMSO wells and expressed asa percent inhibition of apical acid secretion.

TABLE 4 % Inhibition Result (GI Segment) A <50% B 50-70%  C >70% %inhibition % inhibition Example (ileum) (duodenum) 17 B B 23 B B 24 A B26 B B 28 B B 29 C C 31 C C 32 C C 33 C C 34 B B 35 C C 36 C C 41 B C 42C C 43 B C 45 B C 49 C C 52 C C 55 A B 78 C C 91 B C 105 C C 106 C C 107C C 109 C C 110 C C 115 C C 122 C C 123 C C 126 A A

Example 183: Increased Trans-Epithelial Resistance in Human OrganoidMonolayer Cell Cultures

Basal media (BM) consisted of advanced DMEM/F12 containing 10 mM HEPES(Invitrogen, 15630-080), 1:100 Glutamax (Invitrogen, 35050-061), and1:100 penicillin/streptomycin (Invitrogen, 15140-122). Supplementedbasal media (SBM) contained 1:100 N2 (Invitrogen, 17502-048), 1:50 B27(Invitrogen, 12587-010), 1 mM N-acetylcysteine (Sigma, A9165), and 10 nM[Leu15]-gastrin I (Sigma, G9145). Growth factors used included 50 ng permL mouse EGF (Peprotech, 315-09), 100 ng per mL mouse noggin (Peprotech,250-38), 500 ng per mL human R-spondin 1 (R&D, 4645-RS), 100 ng per mLmouse Wnt-3a (R&D, 1324-WN), 20 μM Y-27632 (Tocris, 1254), 10 mMnicotinamide (Sigma, N0636), 500 nM A83-01 (Tocris, 2939), 10 μMSB202190 (Tocris, 1264). Transwells were 0.4 μm pore polyester membrane24-well Transwell inserts (Corning). Cultures were incubated at 37° C.in 5% CO₂.

Human duodenum organoids were cultured in WENRNAS (Wnt, EGF, noggin,R-spondin1, Nicotinamide, A83-01, SB202190) and typically grown for 7-12days before being used to plate monolayer cultures. On day 0, organoidcultures embedded in Matrigel were treated with TrypLE Express to breakorganoids into small pieces and/or single cells. The cells wereresuspended to 0.5×10⁶ cells/mL in SBM containing WENRAY (Wnt, EGF,noggin, R-spondin1, A83-01, Y-27632). Following this step, 200 μL ofcell suspension was plated into the apical side of a 24-well Transwell(100,000 cells/well) and 600 μL of SBM with WENRAY was added to thebasolateral side. Duodenum cells were differentiated with ENA (EGF,noggin, A83-01) on day 3. The color of apical compartment turns frompink or orange to yellow due to the increase in NHE3 expression afterdifferentiation.

Each human duodenum monolayer culture well was washed twice with freshSBM on the apical side on day 6 or day 7 before dosing. All compoundstocks were 10 mM dissolved in DMSO. Each compound stock wasindividually mixed with fresh SBM to reach final compound concentration1 μM and dosed only on the apical side of the monolayer (total volume200 μl). DMSO at the equivalent concentration was used as the vehiclecontrol. Duplicate wells were dosed for each compound. Transepithelialelectrical resistance (TEER) was used as a quantitative technique tomeasure of tight junction permeability. TEER values were recorded(MERS00002, Millipore) before dosing and 30 mins and 1 hr after dosingfor all wells. Each of the duplicate TEER values following treatmentwere corrected for the individual well baseline TEER. Baseline correctedTEER for each example compound was compared to the average of the DMSOwells and expressed as a percent TEER of vehicle control.

TABLE 5 TEER Result (% of vehicle) A <100% B 100-130%   C >130% TEER at30 minutes TEER at 60 minutes Example (% of Vehicle) (% of Vehicle) 17 BB 24 B B 30 B B 31 B C 32 B C 33 B C 41 B B 42 B C 43 B B 91 B B 105 C C106 C C 107 C B 110 C B 115 B B 126 B B

Example 184: Inhibition of Intestinal Sodium Absorption in Mice

Urinary and fecal sodium excretions were measured to assess the abilityof selected example compounds to inhibit the absorption of sodium fromthe intestinal lumen. In addition, an assessment of the absence orpresence of diarrhea in response to compound treatment was made.Approximately eight-week old, male, CD-1 mice were purchased from Envigo(Livermore, Calif.), were housed 6 per cage and acclimated for at least48 hours before study initiation. Animals were fed Harlan Teklad GlobalTD.160470 rodent chow (Maddison, Wis.), standard laboratory rodent chowHarlan Teklad Global 2018 with the addition of 0.4% inorganicphosphorous. Animals had ad libitum access to food and water for theduration of the study and were maintained in a temperature and humiditycontrolled room on a standard light/dark cycle of 6 AM to 6 PM. Toinitiate the study, mice were weighed and then individually placed inmetabolic cages. Following a 3-day acclimation period to the metaboliccage, a 24-hr baseline collection of urine and feces was performed. Mice(n=8/group) were then dosed by oral gavage with test compound (15 mg/kg)or vehicle (3 mM HCl, 0.01% Tween80) at a dose volume of 5 mL/kg, twicedaily at 6 AM and 3 PM for 3 consecutive days. Each day, measurements ofbody weight, 24-hour food intake, water intake, urine volume and wetfecal weight were recorded, along with any observation of diarrhea.Fecal samples were dried using a lyophilizer for at least 3 days,following which dry weight was recorded and fecal fluid content wascalculated based on the difference between the wet and dry stoolweights. Fecal fluid content on day 3 of compound treatment wascalculated as a change from the vehicle group mean. For urine samples,the volumes were determined gravimetrically. Feces and urine wereanalyzed for sodium content by microwave plasma-atomic emissionspectroscopy or ion chromatography, respectively. Urine samples wereanalyzed on an ion chromatography system (Thermo Fisher ICS-3000 orICS-5000+) coupled with conductivity detectors. Chromatographicseparation of cations was performed using an IonPac CS12A (ThermoFisher) 2×250 mm analytical column with an isocratic elution using 25 mMmethanesulfonic acid. Concentrations were interpolated from a a standardcurve (prepared in 10 mM HCl) for sodium ion based on retention time andpeak area. Fecal sample analysis by Microwave Plasma Atomic EmissionSpectrometry (MP-AES). Dry fecal samples were ground into a fine powderon a homogenizer and the ground samples (400-600 mg aliquots weighed)were digested with nitric acid by microwave method (Mars 6). Thesedigested samples were diluted with 1% Nitric acid and analyzed onAgilent 4100 MP-AES. Concentrations were calculated relative to astandard curve (prepared in 1% Nitric acid) for sodium based on thesignal intensity. Sodium was detected at a wavelength of 588.995 nm.Twenty-four-hour urinary sodium excretion (mg/24-hours) was calculatedby multiplying urinary sodium concentration by 24-hour urine volume.Twenty-four-hour fecal sodium excretion (mg/24-hours) was calculated bymultiplying fecal sodium concentration by 24-hour dry fecal weight. Theurinary and fecal sodium excretion on day 3 of compound treatment werenormalized to dietary sodium intake and expressed as a percentage of thevehicle mean.

TABLE 6 Urinary Na Fecal Na Fecal fluid Excretion Excretion content (%of (% of (= from Result vehicle) vehicle) vehicle) A >70% <150%  <5 B50-70%  150-200%   5-10 C <50% >200% >10 Urinary Na Fecal Na Fecal fluidExcretion Excretion content (% of (% of (A from Diarrhea Examplevehicle) vehicle) vehicle) (±) 17 B B B — 23 B B B — 24 B C A — 26 B B B— 27 B C C — 28 A B B — 29 B B A — 30 B C C — 31 B C B — 32 B B A — 33 CC C — 34 B B B — 35 A B A — 36 B B B — 41 C C B — 42 C B B — 43 C C C —45 A A A — 49 A A A — 52 B C B — 53 A A B — 55 A B B — 78 A A A — 88 B BB —

Example 185: Inhibition of Intestinal Sodium Absorption in Rats

Urinary sodium excretion and fecal form were measured to assess theability of selected example compounds to inhibit the absorption ofsodium from the intestinal lumen. Eight-week old, male, Sprague Dawleyrats were purchased from Envigo (Livermore, Calif.), were housed 2 percage and acclimated for at least 48 hours before study initiation.Animals were fed Harlan Teklad Global TD.160470 rodent chow (Maddison,Wis.), standard laboratory rodent chow Harlan Teklad Global 2018 withthe addition of 0.4% inorganic phosphorous. Animals had ad libitumaccess to food and water for the duration of the study and weremaintained in a temperature and humidity controlled room on a standardlight/dark cycle of 6 AM to 6 PM. On the day of study initiation, rats(n=5/group) were dosed by oral gavage with test compound or vehicle (3mM HCl, 0.01% Tween80) at a dose volume of 5 mL/kg. Immediately afterdose administration animals were placed in individual metabolic cages.At 13-hours post-dose, urine samples were collected and fecal form wasassessed. In addition, the weight of food consumed over the 13-hourperiod was measured and recorded. Fecal forms were scored according to acommon scale associated with increasing fecal water to the wettestobservation in the cage's collection funnel (1, normal pellet; 2, pelletadhering to sides of collection funnel due to moisture; 3, loss ofnormal pellet shape; 4, complete loss of shape with a blotting pattern;5, liquid fecal streams evident). Fecal form score (FFS) was calculatedfor each group as the median of each individual rat's FFS within thegroup and reported in Table 7. Fecal samples were dried using alyophilizer for at least 3 days, following which dry weight was recordedand fecal fluid content was calculated based on the difference betweenthe wet and dry stool weights. Fecal fluid content was calculated as achange from the vehicle group mean. For urine samples, the volumes weredetermined gravimetrically. Urine samples were analyzed on an ionchromatography system (Thermo Fisher ICS-3000 or ICS-5000+) coupled withconductivity detectors. Chromatographic separation of cations wasperformed using an IonPac CS12A (Thermo Fisher) 2×250 mm analyticalcolumn with an isocratic elution using 25 mM methanesulfonic acid.Concentrations were interpolated from a standard curve (prepared in 10mM HCl) for sodium based on retention time and peak area.Thirteen-s-hour urinary sodium excretion (mg/13-hours) was calculated bymultiplying urinary sodium concentration by 13-hour urine volume. Theurinary sodium excretion of compound treatment was normalized to dietarysodium intake and expressed as a percentage of the vehicle mean.

TABLE 7 Urinary Na Result (% of Vehicle, out/in) A >70% B 40-70%  C <40%Urinary Na Dose (% of Vehicle, FFS Example (mg/kg) out/in) (1-5) 410.003 A 2 41 0.01 A 2 41 0.03 B 2 41 0.1 C 5 115 0.003 A 1 115 0.01 A 2115 0.03 A 2 115 0.1 C 2 107 0.03 B 3 107 0.1 B 3 107 0.3 C 3 120 0.03 A2 120 0.1 B 3 120 0.3 C 4 132 0.03 A 3 132 0.1 B 3 132 0.3 C 5 123 0.03A 3 123 0.1 B 3 123 0.3 C 3 122 0.03 A 2 122 0.1 A 2 122 0.3 B 3 1330.03 A 3 133 0.1 C 3 133 0.3 C 3 143 0.03 B 3 143 0.1 C 3 143 0.3 C 4

Example 186: Inhibition of Intestinal Sodium and Phosphorous Absorptionin the Rat Balance Model

Urinary and fecal sodium excretion, along with urinary phosphorousexcretion are measured to assess the ability of selected examplecompounds to inhibit the absorption of sodium and phosphorous from theintestinal lumen. In addition, an assessment of fecal form in responseto compound treatment is made. Approximately eight-week old, male,Sprague Dawley rats are purchased from Envigo (Livermore, Calif.),housed 2 per cage and acclimated for at least 48 hours before studyinitiation. Animals are fed Harlan Teklad Global TD.160470 rodent chow(Maddison, Wis.), standard laboratory rodent chow Harlan Teklad Global2018 with the addition of 0.4% inorganic phosphorous. Animals have adlibitum access to food and water for the duration of the study and aremaintained in a temperature and humidity controlled room on a reversedlight/dark cycle of 6 PM to 6 AM. To initiate the study, rats areweighed and individually placed in metabolic cages. Following a 2-dayacclimation period to the metabolic cage, a 24-hr baseline collection ofurine and feces is performed. Rats (n=6/group) are then dosed by oralgavage with test compound or vehicle (3 mM HCl, 0.01% Tween80) at a dosevolume of 5 mL/kg, twice daily at 6 AM and 3 PM for 3 consecutive days.Each day, measurements of body weight, 24-hour food intake, waterintake, urine volume and wet fecal weight are recorded, along with anyobservation of diarrhea. Fecal samples are dried using a lyophilizer forat least 3 days, following which dry weight is recorded and fecal fluidcontent is calculated based on the difference between the wet and drystool weights. Fecal fluid content on day 3 of compound treatment iscalculated as a change from the vehicle group mean. For urine samples,the volumes are determined gravimetrically. Feces and urine are analyzedfor sodium and phosphorous content by microwave plasma-atomic emissionspectroscopy or ion chromatography, respectively. Urine samples areanalyzed on an ion chromatography system (Thermo Fisher ICS-3000 orICS-5000+) coupled with conductivity detectors. Chromatographicseparation of cations is performed using an Ion Pac CS12A (ThermoFisher) 2×250 mm analytical column with an isocratic elution using 25 mMmethanesulfonic acid. Chromatographic separation of anions is performedusing an IonPac AS18 (Thermo Fisher) 2×250 mm analytical column with anisocratic elution using 35 mM potassium hydroxide. Concentrations areinterpolated from a standard curve (prepared in 10 mM HCl) for each ionbased on retention time and peak area. Fecal sample analysis byMicrowave Plasma Atomic Emission Spectrometry (MP-AES). Dry fecalsamples are ground into a fine powder on a homogenizer and the groundsamples (400-600 mg aliquots weighed) are digested with nitric acid bymicrowave method (Mars 6). These digested samples are diluted with 1%Nitric acid and analyzed on Agilent 4100 MP-AES. Concentrations areinterpolated from a standard curve (prepared in 1% Nitric acid) forsodium based on the signal intensity. Sodium is detected at a wavelength01588.995 nm. Twenty-four-hour urinary sodium and phosphorous excretion(mg/24-hours) is calculated by multiplying urinary sodium or phosphorousconcentration, respectively, by 24-hour urine volume. Twenty-four-hourfecal sodium excretion (mg/24-hours) is calculated by multiplying fecalsodium concentration by 24-hour dry fecal weight. The urinary and fecalsodium excretion and urinary phosphorous excretion on day 3 of compoundtreatment are normalized to dietary sodium or phosphorous intake,respectively, and expressed as a percentage of the vehicle mean.

Example 187: Restoration of Gastrointestinal Motility in Opioid InducedConstipation

Gastrointestinal transit is measured in mice treated with theperipherally acting μ-opioid agonist loperamide to assess the ability ofselected example compounds to restore gastrointestinal motility in amodel of opioid induced constipation. Approximately eight-week old,female, CDI rats are purchased from Envigo (Livermore, Calif.), arehoused 4 per cage and acclimated for at least 48 hours before studyinitiation. Animals are fed standard laboratory rodent chow HarlanTeklad Global 2018 (Maddison, Wis.). Animals have ad libitum access tofood and water for the duration of the acclimation period and aremaintained in a temperature and humidity controlled room on a standardlight/dark cycle of 6 AM to 6 PM. Following an overnight fast, with freeaccess to water, animals are dosed by oral gavage with varying doses oftest compound or vehicle (3 mM HCl, 0.01% Tween80), at a dose volume of5 mL/kg. Approximately Fifteen minutes following oral dosing of testcompound or vehicle, animals are dosed by subcutaneous injection withloperamide (0.3 to 6 mg/kg) or vehicle (30:70 PG:0.9% NaCl) at a dosevolume of 5 mL/kg. Fifteen minutes later, animals are dosed orally withEvans Blue Dye (6%) at a dose volume of 100 μL. 30 minutes later,animals are euthanized by carbon dioxide inhalation, and the length fromthe pylorus to cecum (whole length of the small intestine) and thelength from the pylorus to the Evans Blue dye front are measured andrecorded. For an individual animal, the length travels by the Evans Bluedye front is divided by the length of the whole small intestine,measured from the pylorus to the cecum, and multiplied by 100, toprovide the distance of the small intestine travelled by the dye as apercentage. In animals dosed orally with vehicle and injectedsubcutaneously with vehicle (vehicle/vehicle), the Evans Blue dye fronttravels approximately 70% of the length of the small intestine in the30-minute period. In animals dosed orally with vehicle and injectedsubcutaneously with loperamide (vehicle/loperamide), the Evans Blue dyefront travels approximately only 25% of the length of the smallintestine in the 30-minute period, indicating decreased gastrointestinalmotility in response to loperamide. The effect of example compounds onGIT motility in the presence of loperamide is calculated as the abilityto restore vehicle/vehicle transit distance from the vehicle/loperamidetransit, expressed as a percentage.

TABLE 8 % Restoration Result of Transit A <20% B 20-40%  C >40% Dose %Restoration Example (mg/kg) of Transit Standard 15 C 41 15 A 115 15 B132 15 C 123 15 A Standard 15 C 43 15 A 43 1.5 B 43 5 A

Example 188: Restoration of Gastrointestinal Motility in MultipleSclerosis

Gastrointestinal transit time is measured to assess the ability ofselected example compounds to restore gastrointestinal motility in amodel of multiple sclerosis. Multiple sclerosis (MS) patients oftenexperience constipation and other gastrointestinal manifestationsrelated to disturbed gastrointestinal motility. The ExperimentalAutoimmune Encephalomyelitis (EAE) mouse model is one of the mostfrequently used animal models for studying multiple sclerosis (MS), inwhich immunization against CNS-specific antigen results in centralnervous system inflammation. This model results in a spectrum of acute,chronic, and relapsing disease that results in varying degrees ofprogressive paralysis and gastrointestinal dysmotility.

Animals are 8-16 weeks of age at study initiation, and are fed standardlaboratory rodent chow Harlan Teklad Global 2018 (Maddison, Wis.).Animals have ad libitum access to food and water for the duration of thestudy and are maintained in a temperature and humidity controlled roomon a standard light/dark cycle of 6 AM to 6 PM. EAE is induced in femalemice by injection of a combination of antigen (MOG35-55, S.C.) incomplete Freund's adjuvant (CFA), and pertussis toxin (PTX, IP). Aftersomatic motor symptoms develop, generally 10 or more days' postimmunization, EAE mice are dosed by oral gavage with test compound atvarying doses (0.01 to 30 mg/kg) or vehicle (3 mM HCl, 0.01% Tween80) ata dose volume of 5 mL/kg. Test compound is administered for a singledose or twice daily for multiple doses. Fecal output is monitored for astandardized period of time (1-24 hours) and recorded as fecal pelletnumber, fecal mass and fecal dry weight. Whole gastrointestinal transittime is determined by oral gavage of carmine red or Evans Blue andcalculating the latency for dye to appear in the feces. Small intestinaltransit is measured by dosing carmine red or Evans Blue by oral gavageand measuring the distance of the leading edge of the dye from comparedto the whole length of the small intestine 15 minutes to two hoursfollowing oral dosing of the dye. Colonic motility is assessed bymeasuring time to extrusion of a single glass bead inserted astandardized distance into the distal colon. The effect of examplecompounds on GIT motility in EAE mice is calculated as the ability torestore transit distance to those observed in control mice from thoseobserved in EAE treated with vehicle, expressed as a percentage.

Example 189: Restoration of Gastrointestinal Motility in Parkinson'sDisease

Gastrointestinal transit time is measured to assess the ability ofselected example compounds to restore gastrointestinal motility in amodel of Parkinson's disease. Parkinson's disease (PD) is aneurodegenerative disorder characterized by chronic and progressivemotor impairment. PD patients also experience significant non-motorsymptoms including constipation and other gastrointestinalmanifestations related to disturbed gastrointestinal motility. Thetoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has beenwidely used to develop animal models for testing new therapies in thePD. This model results in motor changes and pathology that resemble PDand has also been reported to manifest gastrointestinal dysmotility(Scientific Reports, 2016 6:30269)

Animals are 8-16 weeks of age at study initiation, and fed standardlaboratory rodent chow Harlan Teklad Global 2018 (Maddison, Wis.).Animals have ad libitum access to food and water for the duration of thestudy and are maintained in a temperature and humidity controlled roomon a standard light/dark cycle of 6 AM to 6 PM. PD is induced in mice bymultiple, generally four, intraperitoneal injections of MPTP. After MPTPis injected, generally 4 to 20 days' post injection, PD mice are dosedby oral gavage with test compound at varying doses (0.01 to 30 mg/kg) orvehicle (3 mM 11C1, 0.01% Tween80) at a dose volume of 5 mL/kg. Testcompound is administered once or twice daily for multiple doses. Fecaloutput is monitored for a standardized period of time (1-24 hours) andrecorded as fecal pellet number, fecal mass and fecal dry weight. Wholegastrointestinal transit time is determined by oral gavage of carminered or Evans Blue and calculating the latency for dye to appear in thefeces. Small intestinal transit is measured by dosing carmine red orEvans Blue by oral gavage and measuring the distance of the leading edgeof the dye from compared to the whole length of the small intestine 15minutes to two hours following oral dosing of the dye. Colonic motilityis assessed by measuring time to extrusion of a single glass beadinserted a standardized distance into the distal colon. The effect ofexample compounds on GIT motility in PD mice is calculated as theability to restore transit distance to those observed in control micefrom those observed in PD mice treated with vehicle, expressed as apercentage.

Example 190: Effect on Blood Pressure in a Models of Salt-SensitiveHypertension

Arterial blood pressure is measured to assess the ability of selectedexample compounds to attenuate hypertension in a model of salt-sensitivehypertension. Dahl Salt Sensitive (DSS) rats are a well characterizedmodel of salt-sensitive hypertension and end-organ injury.Salt-sensitive hypertension is established in DSS rats by increasing theNaCl content of the diet from 0.49% up to 4% NaCl for a period of 1 to4-weeks. DSS rats maintained on 0.49% NaCl are used as a control group.Animals are 6-10 weeks of age at study initiation, and have ad libitumaccess to food and water for the duration of the study and aremaintained in a temperature and humidity controlled room on a 12-hrlight/dark cycle. Rats (n=6-8/group) are dosed by oral gavage with testcompound (0.01-30 mg/kg) or vehicle (3 mM HCl, 0.01% Tween80) at a dosevolume of 5 mL/kg, twice daily for 1 to 3 weeks, while maintained on a4% NaCl diet. Arterial blood pressure is measured weekly by tail cuffplethysmography. A 24-hr urine collection is also collected weekly byplacing animals individually in metabolic cages.

Example 191: Effect on Cardiac Function in Models of Heart Failure

Serial echocardiography is used to measure cardiac function andmorphology to assess the ability of selected example compounds toimprove cardiac function, structure and neuro-humoral activation in arat model of heart failure. Male Dahl Salt Sensitive (DSS) rats or maleLewis rats are used to induce heart failure by permanent left maincoronary arterial ligation. Animals are 6-10 weeks of age at studyinitiation, and have ad libitum access to food and water for theduration of the study and are maintained in a temperature and humiditycontrolled room on a 12-hr light/dark cycle. Rats (n=6-10/group) aredosed by oral gavage with test compound (0.01 to 30 mg/kg) or vehicle (3mM HCl, 0.01% Tween80) at a dose volume of 5 mL/kg, twice daily for 1 to8 weeks. Serial echocardiography is performed weekly to assesstime-dependent cardiac remodelling (HWI, LVI, chamber size),time-dependent cardiac performance (EF, dP/dt, LVEDP) changes andtime-dependent cardiac morphometry (HWI, LVI, LVEDV, LVESV) indices.Terminal assessment of load-dependent and load-independent leftventricular function are made using pressure-volume loop analysis.Extracellular volume expansion is assessed by measuring volume sensitivehormones ANP and BNP.

Example 192: Pain Relief in IBS-C—Reduction of Visceral Hypersensitivityin Rats

The ability of selected example compounds to reduce the hypersensitivtyof the colon to balloon distension (CRD) in a rat model of visceralhypersensitivy is measured by grading the rat's abdominal withdrawalreflex (AWR) and by measuring electromyographic (EMG) responses.Visceral hypersensitivity is induced by injecting 10-day old maleSprague Dawley rat pups with a 0.2 mL infusion of 0.5% acetic acidsolution in saline into the colon 2 cm from the anus. Control ratsreceive an equal volume of saline. Visceral hypersensitivity is thenassessed in these rats as adults, between 8 and 12 weeks of age. Rats(n=4-10/group) are dosed by oral gavage with test compound (0.01 to 30mg/kg) or vehicle (3 mM HCl, 0.01% Tween80) at a dose volume of 5 mL/kg,twice daily for up to 2 weeks prior to the assessment of visceralhypersensitivity. Visceral hypersensitivity is measured by grading theresponse to CRD Under mild sedation with 1% methohexital sodium, aflexible balloon attached to Tygon tubing is inserted 8 cm into thedescending colon and rectum via the anus and secured in place by tapingthe tube to the tail. Approximately 30 minutes later, CRD is performedby rapidly inflating the balloon to varying pressures (10 to 80 mmHg)measured by a sphygmomanometer connected to a pressure transducer for a20 second period followed by a 2-minute rest period. Behavioralresponses to CRD are measured by grading the AWR by blinded observer andassigning an AWR score as follows: 1, normal behavior without response;2, contraction of abdominal muscles; 3, lifting of abdominal wall; 4,body arching and lifting of pelvic structures. EMG responses aremeasured continuously in response to CRD via two electrodes implanted atleast one-week prior to in the external oblique muscle and calculated asthe area under the curve of the EMG in response to CRD.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically in this disclosure. Suchequivalents are intended to be encompassed in the scope of the followingclaims.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: Linker is—R¹³—(CHR¹³)_(p)—[Y—(CH₂)_(r)]_(s)—Z—R¹³—(CH₂)_(t)—Z—; X is a bond, H,N, O, CR¹¹R¹², CR¹¹, C, —NHC(O)NH—, —(CHR¹³)_(p)— or C₃-C₆cyclolakyl; Wis independently, at each occurrence, S(O)₂, C(O), or —(CH₂)_(m)—; Z isindependently, at each occurrence, a bond, C(O), or —C(O)NH—; Y isindependently, at each occurrence, O, S, NH, N(C₁-C₃alkyl), or —C(O)NH—;Q is a bond, NH, —C(O)NH—, —NHC(O)NH—, —NHC(O)N(CH₃)—, or—NHC(O)NH—(CHR¹³); m is an integer from 1 to 2; n is an integer from 1to 4; r and p are independently, at each occurrence, integers from 0 to8; s is an integer from 0 to 4; t is an integer from 0 to 4; u is aninteger from 0 to 2; R¹ and R² are independently H, C₁-C₆alkyl,C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl,heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected fromthe group consisting of N, S, P and O, wherein each alkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl isoptionally substituted with one or more halogen, OH, CN, —NO₂, oxo,—SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰, —S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R⁹, —C(O)OR⁹,—C(O)NR⁹R¹⁰, —NR⁹S(O)₂R¹⁰, —S(O)R⁹, —S(O)NR⁹R¹⁰, —NR⁸S(O)R⁹, C₁-C₆alkyl,C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl,heterocyclyl, heterocycle, aryl, or heteroaryl; or R¹ and R² togetherwith the nitrogen to which they are attached can form a heterocyclyl orheteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P and O, wherein the heterocyclyl or heteroaryl group isoptionally substituted with one or more halogen, OH, CN, —NO₂, oxo,—SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰; S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R⁹, —C(O)OR⁹,—C(O)NR⁹R¹⁰; NR⁹S(O)₂R¹⁰, —S(O)R⁹, —S(O)NR⁹R¹⁰, —NR⁹S(O)R¹⁰, C₁-C₆alkyl,C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl,heterocyclyl, heterocycle, aryl, or heteroaryl; R³ and R⁴ areindependently halogen, OH, CN, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl,C₁-C₆haloalkoxy, or —C(O)NR⁹R¹⁰; R⁵, R⁶, R⁷, and R⁸ are independently H,halogen, OH, CN, —NO₂, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl,C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing1-5 heteroatoms selected from the group consisting of N, S, P and O,—SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰, —S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R⁹, —C(O)OR⁹,—NR⁹S(O)₂R¹⁰, —S(O)R⁹, —S(O)NR⁹R¹⁰NR⁸S(O)R⁹; R⁹ and R¹⁰ areindependently H, C₁-C₆alkyl, C₂-C₆alkenyl, C₄-C₈cycloalkenyl,C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroarylcontaining 1-5 heteroatoms selected from the group consisting of N, S, Pand O R¹¹ and R¹² are independently H, C₁-C₆alkyl, OH, NH₂, CN, or NO₂;R¹³ is independently, at each occurrence, a bond, H, C₁-C₆alkyl,C₄-C₈cycloalkenyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroarylis optionally substituted with one or more R¹⁹; R¹⁴ is independently, ateach occurrence, H, C₁-C₆alkyl, or C₁-C₆haloalkyl; or R⁶ and R¹⁴together with the atoms to which they are attached may combine to form,independently, at each occurrence, 5- to-6 membered heterocyclyl,wherein each C₃-C₈ cycloalkyl, or heterocyclyl is optionally substitutedwith one or more R¹⁹; or R¹³ and R¹⁴ together with the atoms to whichthey are attached may combine to form independently, at each occurrence,C₃-C₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P and O, whereineach heterocyclyl or heteroaryl is optionally substituted with one ormore R¹⁹; R¹⁵, R¹⁶, R¹⁷, and R¹⁸ are independently, at each occurrence,H, OH, NH₂, or C₁-C₃ alkyl, wherein the alkyl is optionally substitutedwith one or more R¹⁹; and R¹⁹ are independently, at each occurrence, H,OH, NH₂, oxo, C₁-C₆alkyl, C₁-C₆Hhaloalkyl, C₁-C₆alkoxy; provided that:(1) when X is H, n is 1; (2) when X is a bond, O, or CR¹¹R¹², n is 2;(3) when n is 3, X is CR¹¹ or N; (4) when n is 4 X is C; (5) only one ofQ or X is —NHC(O)NH— at the time, (6) R¹ and R² together with thenitrogen to which they are attached, cannot form a pyrrolidinyl; (7)when R¹ and R² are methyl, R³ and R⁴ are halogen, and R⁵ and R⁸ are H,Linker is not

(8) when R¹ and R² together with the nitrogen to which they are attachedform a piperidinyl, R³ and R⁴ are halogen, and R⁵ and R⁸ are H, Linkeris not and

(9) when R¹ and R², together with the nitrogen to which they areattached, form 3-aminopiperidin-1-yl, R³ and R⁴ are halogen, and R⁵, R⁶,R⁷, and R⁸ are H, Linker is not


2. The compound of claim 1, wherein Linker is selected the groupconsisting of


3. The compound of claim 1, wherein Linker is selected from the groupconsisting of


4. (canceled)
 5. The compound of claim 1, wherein R¹ and R² are methyl.6. (canceled)
 7. The compound of claim 1, wherein R¹ and R² togetherwith the nitrogen to which they are attached can form a heterocyclyl,wherein the heterocyclyl is optionally substituted with one or more oxo.8-32. (canceled)
 33. The compound of claim 1 having the formula Ia:

wherein the ring Het represents R¹ and R² together with the nitrogen towhich they are attached can form a heterocyclyl or heteroaryl containing1-5 heteroatoms selected from the group consisting of N, S, P and O,wherein the heterocyclyl or heteroaryl group is optionally substitutedwith one or more halogen, OH, CN, —NO₂, oxo, —SR⁹, —OR⁹, —NHR⁹, NR⁹R¹⁰,S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R⁹, —C(O)OR⁹, —C(O)NR⁹R¹⁰, NR⁹S(O)₂R¹⁰,—S(O)R⁹, —S(O)NR⁹R₁₀, NR⁹S(O)R¹⁰, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl,heterocycle, aryl, or heteroaryl.
 34. The compound of claim 1 having theformula Ib:

wherein the ring Het represents R¹ and R² together with the nitrogen towhich they are attached can form a heterocyclyl or heteroaryl containing1-5 heteroatoms selected from the group consisting of N, S, P and O,wherein the heterocyclyl or heteroaryl group is optionally substitutedwith one or more halogen, OH, CN, —NO₂, oxo, —SR⁹, —OR⁹, —NHR⁹, —NR⁹R¹⁰,S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R⁹, —C(O)OR⁹, —C(O)NR⁹R¹⁰, NR⁹S(O)₂R¹⁰,—S(O)R⁹, —S(O) NR⁹R¹⁰, NR⁹S(O)R¹⁰, C₁-C₆alkyl, C₂-C₆alkenyl,C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl, heterocyclyl,heterocycle, aryl, or heteroaryl.
 35. The compound of claim 1 having theformula Ic:

wherein Het B represents a C₃-C₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P and O, wherein each heterocyclyl or heteroaryl is optionallysubstituted with one or more R¹⁹.
 36. The compound of claim 1 having theformula Id:

wherein Het is R^(n) which represents C₄-C₈cycloalkenyl,C₃-C₈cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein eachcycloalkenyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl isoptionally substituted with one or more R¹⁹.
 37. The compound of claim 1having the formula Ie:

wherein the ring Het A represents R¹ and R² together with the nitrogento which they are attached can form a heterocyclyl or heteroarylcontaining 1-5 heteroatoms selected from the group consisting of N, S, Pand O, wherein the heterocyclyl or heteroaryl group is optionallysubstituted with one or more halogen, OH, CN, —NO₂, oxo, —SR⁹, —OR⁹,—NHR⁹, —NR⁹R¹⁰, S(O)₂N(R⁹)₂—, —S(O)₂R⁹, —C(O)R⁹, —C(O)OR⁹, —C(O)NR⁹R¹⁰,NR⁹S(O)₂R¹⁰, —S(O)R⁹, —S(O) NR⁹R¹⁰, —NR⁹S(O)R¹⁰, C₁-C₆alkyl,C₂-C₆alkenyl, C₄-C₈cycloalkenyl, C₂-C₆alkynyl, C₃-C₈cycloalkyl,heterocyclyl, heterocycle, aryl, or heteroaryl; and Het is R¹³ whichrepresents C₄-C₈cycloalkenyl, C₃-C₈cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein each cycloalkenyl, cycloalkyl, heterocyclyl, aryl,or heteroaryl is optionally substituted with one or more R¹⁹.
 38. Thecompound of claim 1 having the formula If:


39. The compound of claim 1 having the formula If:


40. The compound of claim 1 having the formula Ig:


41. The compound of claim 1 having the formula Ih: wherein:

Het represents R⁶ and R¹⁴ together with the atoms to which they areattached forming, independently, at each occurrence, a 5- to-6 memberedheterocyclyl.
 42. The compound of claim 1 having the formula Ii:


43. The compound of claim 1 selected from the group consisting of:3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl] carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl] urea;3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dim ethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;1-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl] carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;1-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]ureadihydrochloride;3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-/H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-(4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-(4-([(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-[[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl] pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea;3-[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea;3-[(4-[[(3S)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea;3-[(4-[[(3R)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea;3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;1-([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-3-(4-[[([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)carbamoyl]amino]butyl)urea;(2R,3S,4R,5S)—N¹,N⁶-Bis([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-2,3,4,5-tetrahydroxyhexanediamide;3-[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)methyl]-1-[4-([[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)methyl]carbamoyl]amino)butyl]urea;3-[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]hexyl]-1H-1,2,3-triazol-4-yl)methyl]-1-[4-([[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]hexyl]-1H-1,2,3-triazol-4-yl)methyl]carbamoyl]amino)butyl]urea;(4R,4aS,8S,8aR)—N⁴,N⁸-Bis([1-(4-[4-((1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenylsulfonamide]butyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-tetrahydro-[1,3]dioxino[5,4-d][1,3]dioxine-4,8-dicarboxamide;(4R,4aS,8 S,8aR)—N⁴,N⁸-Bis([1-(6-[4-((1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenylsulfonamido]hexyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-tetrahydro-[1,3]dioxino[5,4-d][1,3]dioxine-4,8-dicarboxamide;3-[8-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea;3-[8-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea;3-[8-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea;3-[8-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]octyl]carbamoyl)amino]butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(2S)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2S)-2-methylpiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-2-[2-Azabicyclo[2.2.1]heptan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.1]heptan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;1-[2-(2-[2-[(4-[[(1S,2S)-2-[2-Azabicyclo[2.2.2]octan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.2]octan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.2.1]octan-8-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.2.1]octan-8-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;1-[2-(2-[2-[(4-[[(1S,2S)-2-[9-Azabicyclo[3.3.1]nonan-9-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[9-azabicyclo[3.3.1]nonan-9-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-Acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-Acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;4-[(1S,2S)-4,6-dichloro-1-[4-[(2-[2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[4-(dimethylcarbamoyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)ethoxy]ethoxy]ethyl)sulfamoyl]phenoxy]-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperazine-1-carboxamide;4-[(1S,2S)-4,6-dichloro-1-[4-[(2-[2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[4-(dimethylcarbamoyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)ethoxy]ethoxy]ethyl)sulfamoyl]-2-methylphenoxy]-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperazine-1-carboxamide;3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;hydrochloride;1-[2-(2-[2-[(3-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,4-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;hydrochloride;1-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-difluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-difluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3,5-difluorophenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]-3,5-difluorobenzenesulfonamide;3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]piperidin-4-yl]oxy)ethoxy]ethyl]-1-[4-[([2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]piperidin-4-yl]oxy)ethoxy]ethyl]carbamoyl)amino]butyl]urea;1-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-3-(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea;hydrochloride;3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea;3-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]amino]butyl)ureadihydrochloride;3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea;1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-2-methylpropoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-2-methylpropoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;hydrochloride;1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;4-(1S,2S)-2-[(R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-2-[(R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy)-2-chlorophenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]-2-chlorobenzenesulfonamide;4-([(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide;tetra(trifluoroacetate);4-([(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide;tetra(trifluoroacetate);4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;tetra(trifluoroacetate);4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;tetra(trifluoroacetate);4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide;tetra(trifluoroacetate);4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamide)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide;tetra(trifluoroacetate);4-(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)-3-fluorobenzenesulfonamide;tetra(trifluoroacetate);4-(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)-3-fluorobenzenesulfonamide;tetra(trifluoroacetate);4-([(1S,2S)-6-Chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamide;tetra(trifluoroacetate);4-([(1S,2S)-6-Chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamide;tetra(trifluoroacetate);4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide;4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl)pyrrolidin-3-yl]benzenesulfonamide;4-(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-[(2S,13S)-14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2,13-dimethyl-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl]pyrrolidin-3-yl]benzenesulfonamide;N¹,N¹⁴-bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;N¹,N¹⁴-bis(2-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;N¹,N¹⁸-Bis(1-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)piperidin-4-yl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide;4-(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-(1S,2S)-6-chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide;-(1S,2S)-6-Chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-(1S,2S)-6-chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide;4-(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamide]piperidin-1-yl)-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl]piperidin-4-yl)benzenesulfonamide;N¹,N¹⁸-Bis([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-6,13-dioxo-5,7,12,14-tetraazaoctadecanediamide;N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-1-[16-(4-[([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)carbamoyl]piperidin-1-yl)-5,12-dioxo-4,6,11,13-tetraazahexadecyl]piperidine-4-carboxamide;4-(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-′7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(5)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;4-(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(5)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;4-(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;4-(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(5)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-2-oxopiperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)-2-oxopiperidin-3-yl]benzenesulfonamide;4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[2-(2-[2-(3-[(1r,4r)-4-(3-[2-(2-[2-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)ethoxy]ethoxy)ethyl]ureido)cyclohexyl]ureido)ethoxy]ethoxy)ethyl]benzenesulfonamide;4-(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(R)-1-(18-(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide;4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide;N-(2-[2-(2-Aminoethoxy)ethoxy]ethyl)-4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide;N-[1-(4-Aminobutanoyl)piperidin-4-yl]-4-(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide;4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-(3-oxo-7,10-dioxa-2,4-diazadodecan-12-yl)benzenesulfonamide;4-(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-(1-[4-(3-methylureido)butanoyl]piperidin-4-yl)benzenesulfonamide;4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-yl]benzenesulfonamide;4-([4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-yl]piperidine-1-carboxamide;4-(3-[4-([4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-4-oxobutyl]ureido)-N-([4-(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)butanamide;4-(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(4-[3-(4-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-4-oxobutyl)ureido]butanoyl)piperidin-4-yl]benzenesulfonamide;4-(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[19-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecyl]benzenesulfonamide;4-([(1S,2S)-6-Chloro-4-amido-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-amido-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide;4-([(1S,2S)-4-Cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-4-cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfonamide;1,1′-(Butane-1,4-diyl)bis[3-(4-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinolin-2(1H)-yl]-4-oxobutyl)urea];1,1′-(Butane-1,4-diyl)bis[3-(4-[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinolin-2(1H)-yl]-4-oxobutyl)urea];N,N-(6,14-Dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[6-(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide];N,N-(6,14-Dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[7-(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinoline-2(1H)-carboxamide];4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(S)-1-(18-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide;4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[(R)-1-(18-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamide;4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide;N¹,N¹⁴-Bis(2-[(S)-3-[(S)-(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)piperidin-4-yl]benzenesulfonamide;4-([(1S,2S)-4,6-Dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N—[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;N¹,N¹⁴-Bis(2-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;1,1′-(Butane-1,4-diyl)bis(3-[2-(2-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindolin-2-yl]ethoxy)ethyl]urea);and1,1′-(Butane-1,4-diyl)bis(3-[2-(2-[5-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindolin-2-yl]ethoxy)ethyl]urea).(1S,2S)-1-(4-{(3S)-1-[2-(2-{[(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-4-carboxy-6-chloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)-1-hydroxy-1λ⁴-pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)carbamoyl]amino}ethoxy)ethyl]-1-hydroxy-1λ⁴-pyrrolidin-3-yl]sulfamoyl}phenoxy)-6-chloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-indene-4-carboxylicacid; 3-(2-{2-[(3S)-3-(4-{[(1 S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}(2,3,5,6-²H₄)benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}(2,3,5,6-²H₄)benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}(1, 1,2,2,3,3,4,4-²H₈)butyl)urea; 3-(2-{2-[2-(4-{[(1 S,2S)-4-cyano-6-methyl-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-4-cyano-6-methyl-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea;3-(2-{2-[(3 S)-3-(4-{[(1 S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-[(1 S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxyethyl)carbamoyl]amino}butyl)urea; N-{2-[(3 S)-3-(4-{[(1 S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}-2-({[4-({[({2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}carbamoyl)methyl]carbamoyl}amino)butyl]carbamoyl}amino)acetamide;3-(2-{2-[2-(4-{[(1 S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-[(1s,4 s)-4-{[(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxyethyl)carbamoyl]amino}cyclohexyl]urea; 1,3-bis(2-{2-[2-(4-{[(1 S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)urea;4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-N-[19-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecyl]benzenesulfonamide;3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-[(1r,4r)-4-[(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}cyclohexyl]urea;3-(2-{2-[(3 S)-3-(4-{[(1 S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxyethyl)-1-(4-{[(2-{2-[(3 S)-3-(4-[(1 S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}(1,1,2,2,3,3,4,4-²H₈)butyl)urea; 3-{4-[(3 S)-3-(4-{[(1 S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-4-oxobutyl}-1-{4-[({4-[(3S)-3-(4-{[(1 S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-4-oxobutyl}carbamoyl)amino]butyl}urea;3-{4-[4-(4-{[(1 S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)piperidin-1-yl]-4-oxobutyl}-1-{4-[({4-[4-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)piperidin-1-yl]-4-oxobutyl}carbamoyl)amino]butyl}urea;N-{2-[(3R)-3-(4-{[(1 S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl-2-([Lk{R{2-[(3R)-3-(4-{[(1 S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}carbamoyl)methyl]carbamoyl}amino)butyl]carbamoyl}amino)acetamide;3-(2-{2-[4-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)piperidin-1-yl]ethoxyethyl)-1-(4-{[(2-{2-[4-(4-{[(1 S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)piperidin-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)urea;3-{2-[(3 S)-3-(4-{[(1 S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}-1-{4-R{2-[(3 S)-3-(4-{[(1 S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}carbamoyl)amino]butyl}urea;and (3 S)—N-(4-{[(1 S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonyl)-1-[2-(2-{[(4-{[(2-{2-[(3S)-3-[(4-{[(1 S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonyl)carbamoyl]pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)carbamoyl]amino}ethoxy)ethyl]pyrrolidine-3-carboxamide.44. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 45. A method for inhibitingNHE-mediated antiport of sodium and hydrogen ions, the method comprisingadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound or pharmaceutical composition of claim
 1. 46. Amethod for treating a disorder associated with fluid retention or saltoverload, the method comprising administering to a mammal in needthereof a pharmaceutically effective amount of a compound orpharmaceutical composition of claim
 1. 47. The method of claim 46,wherein the disorder is selected from the group consisting ofgastrointestinal motility disorder, irritable bowel syndrome, chronicconstipation, chronic idiopathic constipation, chronic constipationoccurring in cystic fibrosis, opioid-induced constipation, chronicintestinal pseudo-obstruction, colonic pseudo-obstruction, ulcerativecolitis, inflammatory bowel disease, gastrointestinal tract disorder isassociated with chronic kidney disease (stage 4 or 5), constipationinduced by calcium supplement, constipation associated with the use of atherapeutic agent, constipation associated with a neuropathic disorder(Parkinson's disease, multiple sclerosis), post-surgical constipation(postoperative ileus), idiopathic constipation (functional constipationor slow transit constipation), constipation associated with neuropathic,metabolic or an endocrine disorder, constipation due the use of drugsselected from analgesics (e.g., opioids), antihypertensive,anticonvulsants, antidepressants, antispasmodics and antipsychotics,gastric ulcers, infectious diarrhea, leaky gut syndrome, cystic fibrosisgastrointestinal disease, microscopic colitis, necrotizingenterocolitis, atopy, food allergy, acute inflammation, chronicinflammation, obesity-induced metabolic diseases, kidney disease,chronic kidney disease, diabetic kidney disease, heart disease, heartfailure, congestive heart failure, hypertension, essential hypertension,primary hypertension, salt-sensitive hypertension, liver disease,cirrhosis, nonalcoholic steatohepatitis, nonalcoholic fatty liverdisease, steatosis, primary sclerosing cholangitis, primary biliarycholangitis, portal hypertension, Type 1 diabetes, celiac disease,multiple sclerosis, ankylosing spondylitis, rheumatoid arthritis, lupus,alopecia areata, polymyalgia rheumatica, multiple sclerosis,fibromyalgia, chronic fatigue syndrome, Sjogren's syndrome, vitiligo,thyroiditis, vasculitis, Crohn's disease, ulcerative colitis, urticaria(hives), Raynaud's syndrome, schizophrenia, autism spectrum disorders,multiple sclerosis, hepatic encephalopathy, small intestinal bacterialovergrowth, secondary hyperparathyroidism (PTH), celiac disease,hyperphosphatemia and chronic alcoholism. 48-57. (canceled)